Reelin
Encyclopedia
Reelin is a large secreted extracellular matrix
protein
that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates the synaptic plasticity
by enhancing the induction and maintenance of long-term potentiation
. It also stimulates dendrite and dendritic spine
development and regulates the continuing migration of neuroblast
s generated in adult neurogenesis sites like subventricular
and subgranular zone
s. It is found not only in the brain
, but also in the spinal cord
, blood
, and other body organs and tissues.
Reelin has been suggested to be implicated in pathogenesis of several brain diseases. The expression of the protein has been found to be significantly lower in schizophrenia
and psychotic bipolar disorder
, but the cause of this observation remains uncertain as studies show that psychotropic medication itself affects reelin expression. Moreover, the epigenetic hypothesis aimed at explaining the changed levels has received some contradictory evidence. Total lack of reelin causes a form of lissencephaly
. Reelin may also play a role in Alzheimer's disease
, temporal lobe epilepsy
and autism
.
Reelin's name comes from the abnormal reeling gait
of reeler
mice, which were later found to have a deficiency of this brain protein
and were homozygous
for mutation of the RELN gene.
The primary phenotype associated with loss of reelin function is a failure of neuronal positioning throughout the developing central nervous system
(CNS). The mice heterozygous
for the reelin gene, while having little neuroanatomical defects, display the endophenotypic
traits linked to psychotic disorders.
Mutant mice have provided insight into the underlying molecular mechanisms of the development of the central nervous system
. Useful spontaneous mutations were first identified by scientists who were interested in motor behavior, and it proved relatively easy to screen littermates for mice that showed difficulties moving around the cage. A number of such mice were found and given descriptive names such as reeler, weaver, lurcher, nervous, and staggerer.
The "reeler
" mouse was described for the first time in 1951 by D.S.Falconer
in Edinburgh University as a spontaneous variant arising in a colony of mice maintained by geneticist Charlotte Auerbach
. Histopathological
studies in the 1960s revealed that the cerebellum
of reeler mice is dramatically decreased in size while the normal laminar organization found in several brain regions is disrupted. The 1970s brought the discovery of cellular layers inversion in the mice neocortex, which attracted more attention to the reeler mutation.
In 1994, a new allele
of reeler was obtained by means of insertional mutagenesis
. This provided the first molecular marker of the locus
, permitting the RELN gene to be mapped to chromosome 7q22 and subsequently cloned and identified. Japanese scientists at Kochi Medical School successfully raised antibodies against normal brain extracts in reeler mice, later these antibodies were found to be specific monoclonal antibodies
for reelin, and were termed CR-50 (Cajal-Retzius marker 50). They noted that CR-50 reacted specifically with Cajal-Retzius neurons
, whose functional role was unknown until then.
The Reelin receptors, apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), were discovered by Trommsdorff, Herz and colleagues, who initially found that the cytosolic adaptor protein Dab1 interacts with the cytoplasmic domain of LDL receptor family members. They then went on to show that the double knockout
mice for ApoER2 and VLDLR, which both interact with Dab1, had cortical layering defects similar to those in reeler.
The downstream
pathway
of reelin was further clarified with the help of other mutant mice, including yotari
and scrambler
. These mutants have phenotypes similar to that of reeler mice, but without mutation in reelin. It was then demonstrated that the mouse disabled homologue 1 (Dab1
) gene is responsible for the phenotypes of these mutant mice, as Dab1 protein was absent (yotari) or only barely detectable (scrambler) in these mutants. Targeted disruption of Dab1 also caused a phenotype similar to that of reeler. Pinpointing the DAB1
as a pivotal regulator of the reelin signaling cascade started the tedious process of deciphering its complex interactions.
There followed a series of speculative reports linking reelin's genetic variation and interactions to schizophrenia, Alzheimer's disease, autism and other highly complex dysfunctions. These and other discoveries, coupled with the perspective of unraveling the evolutionary changes that allowed for the creation of human brain, highly intensified the research. As of 2008, some 13 years after the gene coding the protein was discovered, hundreds of scientific articles address the multiple aspects of its structure and functioning.
Studies show that reelin is absent from synaptic vesicle
s and is secreted via constitutive secretory pathway
, being stored in Golgi
secretory vesicles. Reelin's release rate is not regulated by depolarization
, but strictly depends on its synthesis rate. This relationship is similar to that reported for the secretion of other extracellular matrix
proteins.
During the brain development, reelin is secreted in the cortex and hippocampus by the so-called Cajal-Retzius cell
s, Cajal cells, and Retzius cells. Reelin-expressing cells in the prenatal and early postnatal brain are predominantly found in the marginal zone (MZ) of the cortex and in the temporary subpial granular layer (SGL), which is manifested to the highest extent in human, and in the hippocampal stratum lacunosum-moleculare and the upper marginal layer of the dentate gyrus
.
In the developing cerebellum
, reelin is expressed first in the external granule cell
layer (EGL), before the granule cell migration to the internal granule cell layer (IGL) takes place.
Having peaked just after the birth, the synthesis of reelin subsequently goes down sharply, becoming more diffuse compared with the distinctly laminar expression in the developing brain. In the adult brain, reelin is expressed by GABA
-ergic interneuron
s of the cortex and glutamatergic cerebellar neurons, and by the few extant Cajal-Retzius cells. Among GABAergic interneurons, reelin seems to be detected predominantly in those expressing calretinin
and calbindin
, like bitufted, horizontal, and Martinotti cell
s, but not parvalbumin
-expressing cells, like chandelier
or basket neurons. In the white matter, a minute proportion of interstitial neurons has also been found to stain positive for reelin expression.
Outside the brain, reelin is found in adult mammalian blood, liver
, pituitary pars intermedia
, and adrenal chromaffin cell
s. In the liver, reelin is localized in hepatic stellate cell
s. The expression of reelin increases when the liver is damaged, and returns to normal following its repair.
In the eyes, reelin is secreted by retinal ganglion cells and is also found in the endothelial layer of the cornea
. Just as in the liver, its expression increases after an injury has taken place.
The protein is also produced by the odontoblast
s, which are cells at the margins of the dental pulp. Reelin is found here both during odontogenesis and in the mature tooth. Some authors suggest that odontoblasts play an additional role as sensory cells able to transduce
pain signals to the nerve endings. According to the hypothesis, reelin participates in the process by enhancing the contact between odontoblasts and the nerve terminals.
Reelin is a secreted extracellular matrix
glycoprotein
composed of 3461 amino acids with a relative molecular mass of 388 kDa
. It also has serine protease
activity. Murine RELN gene consists of 65 exon
s spanning approximately 450 kb
. One exon, coding for only two amino acids near the protein's C-terminus, undergoes alternative splicing
, but the exact functional impact of this is unknown. Two transcription initiation sites and two polyadenylation sites are identified in the gene structure.
The reelin protein starts with a signaling peptide 27 amino acids in length, followed by a region bearing similarity to F-spondin
(the reeler domain
), marked as "SP" on the scheme, and by a region unique to reelin, marked as "H". Next comes 8 repeats of 300-350 amino acids. These are called reelin repeats and have an epidermal growth factor
motif at their center, dividing each repeat into two subrepeats, A (the BNR/Asp-box repeat
) and B (the EGF-like domain
). Despite this interruption, the two subdomains make direct contact, resulting in a compact overall structure.
The final reelin domain contains a highly basic and short C-terminal region (CTR, marked "+") with a length of 32 amino acids. This region is highly conserved, being 100% identical in all investigated mammals. It was thought that CTR is necessary for reelin secretion, because the Orleans reeler
mutation, which lacks a part of 8th repeat and the whole CTR, is unable to secrete the misshaped protein, leading to its concentration in cytoplasm. However, other studies have shown that the CTR is not essential for secretion itself, but mutants lacking the CTR were much less efficient in activating downstream signaling events.
Reelin is cleaved in vivo at two sites located after domains 2 and 6 – approximately between repeats 2 and 3 and between repeats 6 and 7, resulting in the production of three fragments. This splitting does not decrease the protein's activity, as constructs made of the predicted central fragments (repeats 3–6) bind to lipoprotein receptors, trigger Dab1
phosphorylation
and mimic functions of reelin during cortical plate development. Moreover, the processing of reelin by embryonic neurons may be necessary for proper corticogenesis.
The primary functions of Reelin are the regulation of corticogenesis and neuronal cell positioning in the prenatal period, but the protein is also continues to play a role in adults. Reelin is found in numerous tissues and organs, and one could roughly subdivide its functional roles by the time of expression and by localisation of its action.
and affects the orientation of its fibers, which serve as the guides for the migrating neuroblasts. The position of reelin-secreting cell layer is important, because the fibers orient themselves in the direction of its higher concentration. For example, reelin regulates the development of layer-specific connections in hippocampus and entorhinal cortex.
Mammalian corticogenesis is another process where reelin plays a major role. In this process the temporary layer called preplate is split into the marginal zone on the top and subplate below, and the space between them is populated by neuronal layers in the inside-out pattern. Such an arrangement, where the newly created neurons pass through the settled layers and position themselves one step above, is a distinguishing feature of mammalian brain, in contrast to the evolutionary older reptile cortex, in which layers are positioned in an "outside-in" fashion. When reelin is absent, like in the mutant reeler
mouse, the order of cortical layering becomes roughly inverted, with younger neurons finding themselves to be unable to pass the settled layers. Subplate neurons fail to stop and invade the upper most layer, creating the so-called superplate in which they mix with Cajal-Retzius cell
s and some cells normally destined for the second layer.
There is no agreement concerning the role of reelin in the proper positioning of cortical layers. The original hypothesis, that the protein is a stop signal for the migrating cells, is supported by its ability to induce the dissociation, its role in asserting the compact granule cell layer in the hippocampus, and by the fact that migrating neuroblasts evade the reelin-rich areas. But an experiment in which murine corticogenesis went normally despite the malpositioned reelin secreting layer, and lack of evidence that reelin affects the growth cones and leading edges of neurons, caused some additional hypotheses to be proposed. According to one of them, reelin makes the cells more susceptible to some yet undescribed positional signaling cascade.
Reelin may also ensure correct neuronal positioning in the spinal cord
: according to one study, location and level of its expression affects the movement of sympathetic preganglionic neurons.
The protein is thought to act on migrating neuronal precursors and thus controls correct cell positioning in the cortex and other brain structures. The proposed role is one of a dissociation signal for neuronal groups, allowing them to separate and go from tangential chain-migration to radial individual migration. Dissociation detaches migrating neurons from the glial cell
s that are acting as their guides, converting them into individual cells that can strike out alone to find their final position.
Reelin takes part in the developmental change of NMDA receptor
configuration, increasing mobility of NR2B-containing receptors and thus decreasing the time they spend at the synapse
. It has been hypothesized that this may be a part of the mechanism behind the "NR2B-NR2A switch" that is observed in the brain during its postnatal development. Ongoing reelin secretion by GABAergic hippocampal neurons is necessary to keep NR2B-containing NMDA receptors at a low level.
(RMS) to reach the olfactory bulb, where reelin dissociates them into individual cells that are able to migrate further individually. They change their mode of migration from tangential to radial, and begin using the radial glia fibers as their guides. There are studies showing that along the RMS itself the two receptors, ApoER2 and VLDLR, and their intracellular adapter DAB1
function independently of Reelin, most likely by the influence of a newly proposed ligand, thrombospondin-1. In the adult dentate gyrus, reelin provides guidance cues for new neurons that are constantly arriving to the granule cell layer from subgranular zone, keeping the layer compact.
Reelin also plays an important role in the adult brain by modulating cortical pyramidal neuron dendritic spine
expression density, the branching of dendrite
s, and the expression of long-term potentiation
as its secretion is continued diffusely by the GABAegric cortical interneurons those origin is traced to the medial ganglionic eminence
.
In the adult organism the non-neural expression is much less widespread, but goes up sharply when some organs are injured. The exact function of reelin upregulation following an injury is still being researched.
Reelin-DAB1 interactions could have played a key role in the structural evolution of the cortex that evolved from a single layer in the common predecessor of the amniote
s into multiple-layered cortex of contemporary mammals. Research shows that reelin expression goes up as the cortex becomes more complex, reaching the maximum in the human brain in which the reelin-secreting Cajal-Retzius cells have significantly more complex axonal arbour. Reelin is present in the telencephalon of all the vertebrates studied so far, but the pattern of expression differs widely. For example, zebrafish have no Cajal-Retzius cells at all; instead, the protein is being secreted by other neurons. These cells do not form a dedicated layer in amphibians, and radial migration in their brains is very weak.
As the cortex becomes more complex and convoluted, migration along the radial glia fibers becomes more important for the proper lamination. The emergence of a distinct reelin-secreting layer is thought to play an important role in this evolution. There are conflicting data concerning the importance of this layer, and these are explained in the literature either by the existence of an additional signaling positional mechanism that interacts with the reelin cascade, or by the assumption that mice that are used in such experiments have redundant secretion of reelin compared with more localized synthesis in the human brain.
Cajal-Retzius cells, most of which disappear around the time of birth, coexpress reelin with the HAR1 gene that is thought to have undergone the most significant evolutionary change in humans compared with chimpanzee, being the most "evolutionary accelerated" of the genes from the human accelerated regions
. There is also evidence of that variants in the DAB1 gene have been included in a recent selective sweep in Chinese populations.
: VLDLR
and the ApoER2
. The two main reelin receptors seem to have slightly different roles: VLDLR conducts the stop signal, while ApoER2 is essential for the migration of late-born neocortical neurons. It also has been shown that the N-terminal region of reelin, a site distinct from the region of reelin shown to associate with VLDLR/ApoER2 binds to the alpha-3-beta-1 integrin
receptor. The proposal that the protocadherin
CNR1 behaves as a Reelin receptor has been disproven.
As members of lipoprotein receptor superfamily, both VLDLR and ApoER2 have in their structure an internalization domain called NPxY motif
. After binding to the receptors reelin is internalized by endocytosis
, and the N-terminal fragment of the protein is re-secreted. This fragment may serve postnatally to prevent apical dendrites of cortical layer II/III pyramidal neurons from overgrowth, acting via a pathway independent of canonical reelin receptors.
Reelin receptors are present on both neuron
s and glial cell
s. Furthermore radial glia
express the same amount of ApoER2
but being ten times less rich in VLDLR
. beta-1 integrin receptors
on glial cells play more important role in neuronal layering than the same receptors on the migrating neuroblasts.
Reelin-dependent strengthening of long-term potentiation
is caused by ApoER2 interaction with NMDA receptor
. This interaction happens when ApoER2 has a region coded by exon 19. ApoER2 gene is alternatively spliced, with the exon 19-containing variant more actively produced during periods of activity. According to one study, the hippocampal reelin expression rapidly goes up when there is need to store a memory, as demethylase
s open up the RELN gene. The activation of dendrite growth by reelin is apparently conducted through Src
family kinase
s and is dependent upon the expression of Crk
family proteins, consistent with the interaction of Crk and CrkL with tyrosine-phosphorylated Dab1. Moreover, a Cre-loxP recombination
mouse model that lacks Crk
and CrkL
in most neurons was reported to have the reeler
phenotype, indicating that Crk/CrkL lie between DAB1
and Akt
in the reelin signaling chain.
, inducing the expression of FABP7
and prompting progenitor cells to assume radial glia
l phenotype. In addition, corticogenesis in vivo is highly dependent upon reelin being processed by embrionic neurons, which are thought to secrete some as yet unidentified metalloproteinase
s that free the central signal-competent part of the protein. Some other unknown proteolytic mechanisms may also play a role. It is supposed that full-sized reelin sticks to the extracellular matrix fibers on the higher levels, and the central fragments, as they are being freed up by the breaking up of reelin, are able to permeate into the lower levels. It is possible that as neuroblast
s reach the higher levels they stop their migration either because of the heightened combined expression of all forms of reelin, or due to the peculiar mode of action of the full-sized reelin molecules and its homodimers.
The intracellular adaptor DAB1
binds to the VLDLR and ApoER2 through an NPxY motif and is involved in transmission of Reelin signals through these lipoprotein receptors. It becomes phosphorylated by Src
and Fyn
kinases and apparently stimulates the actin
cytoskeleton to change its shape, affecting the proportion of integrin receptors on the cell surface, which leads to the change in adhesion
. Phosphorylation of DAB1 leads to its ubiquitination and subsequent degradation, and this explains the hightened levels of DAB1 in the absence of reelin. Such negative feedback
is thought to be important for proper cortical lamination. Activated by two antibodies, VLDLR and ApoER2 cause DAB1 phosphorylation but seemingly without the subsequent degradation and without rescuing the reeler
phenotype, and this may indicate that a part of the signal is conducted independently of DAB1.
A protein having an important role in lissencephaly
and accordingly called LIS1 (PAFAH1B1
), was shown to interact with the intracellular segment of VLDLR, thus reacting to the activation of reelin pathway.
homodimer. If the homodimer fails to form, efficient tyrosine phosphorylation
of DAB1 in vitro fails. Moreover, the two main receptors of reelin are able to form clusters that most probably play a major role in the signaling, causing the intracellular adaptor DAB1 to dimerize or oligomerize in its turn. Such clustering has been shown in the study to activate the signaling chain even in the absence of Reelin itself. In addition, reelin itself can cut the peptide bonds holding other proteins together, being a serine protease
, and this may affect the cellular adhesion and migration processes. Reelin signaling leads to phosphorylation of actin
-interacting protein cofilin 1
at ser3; this may stabilize the actin cytoskeleton and anchor the leading processes of migrating neuroblasts, preventing their further growth.
(Cdk5), a major regulator of neuronal migration and positioning, is known to phosphorylate DAB1
and other cytosolic targets of reelin signaling, such as Tau
, which could be activated also via reelin-induced deactivation of GSK3B
, and NUDEL
, associated with Lis1
, one of the DAB1 targets. LTP
induction by reelin in hippocampal slices fails in p35
knockouts. P35 is a key Cdk5 activator, and double p35/Dab1, p35/RELN, p35/ApoER2, p35/VLDLR knockouts display increased neuronal migration deficits, indicating a synergistic action of reelin → ApoER2/VLDLR → DAB1 and p35/p39 → Cdk5 pathways in the normal corticogenesis.
with cerebellar hypoplasia
called Norman-Roberts syndrome
. The mutations disrupt splicing
of the RELN mRNA
transcript, resulting in low or undetectable amounts of reelin protein. The phenotype
in these patients was characterized by hypotonia
, ataxia
, and developmental delay, with lack of unsupported sitting and profound mental retardation with little or no language development. Seizures and congenital lymphedema
are also present. A novel chromosomal translocation
causing the syndrome was described in 2007. The mutations affecting reelin in human are usually associated with consanguineous marriage
.
levels in the brains of schizophrenia
sufferers had been reported in 1998 and 2000 and independently confirmed in the postmortem studies of hippocampus, cerebellum
, basal ganglia
, and in the cortex studies. The reduction may reach up to 50% in some brain regions and is coupled with reduced expression of GAD-67 enzyme
, which catalyses the transition of glutamate to GABA
. Blood levels
of reelin and its isoforms are also altered in schizophrenia, along with mood disorder
s, according to one study. Reduced reelin mRNA prefrontal expression in schizophrenia was found to be the most statistically relevant disturbance found in the multicenter study conducted in 14 separate laboratories in 2001 by Stanley Foundation Neuropathology Consortium.
Epigenetic
hypermethylation of DNA in schizophrenia patients is proposed as a cause of the reduction, in agreement with the observations dating from the 1960s that administration of methionine
to schizophrenic patients results in a profound exacerbation of schizophrenia symptoms in sixty to seventy percent of patients. The proposed mechanism is a part of the "epigenetic hypothesis for schizophrenia pathophysiology" formulated by a group of scientists in 2008 (D. Grayson; A. Guidotti; E. Costa
). A postmortem study comparing a DNA methyltransferase
(DNMT1) and Reelin mRNA expression in cortical layers I and V of schizophrenic patients and normal controls demonstrated that in the layer V both DNMT1 and Reelin levels were normal, while in the layer I DNMT1 was threefold higher, probably leading to the twofold decrease in the Reelin expression. There is evidence that the change is selective, and DNMT1 is overexpressed in reelin-secreting GABAegric neurons but not in their glutamatergic neighbours. Methylation
inhibitors and histone deacetylase
inhibitors, such as valproic acid
, increase reelin mRNA levels, while L-methionine treatment downregulates the phenotypic expression of reelin. One study indicated the upregulation of histone deacetylase HDAC1 in the hippocampi of patients. Histone deacetylases suppress gene promoters; hyperacetylation of hystones was shown in murine models to demethylate the promoters of both reelin and GAD67. DNMT1 inhibitors in animals have been shown to increase the expression of both reelin and GAD67, and both DNMT inhibitors and HDAC inhibitors shown in one study to activate both genes with comparable dose- and time-dependence. As one study shows, S-adenosyl methionine
(SAM) concentration in patients' prefrontal cortex is twice as high as in the cortices of non-affected people. SAM, being a methyl group donor necessary for DNMT activity, could further shift epigenetic control of gene expression.
The factors mentioned above serve to corroborate the epigenetic hypothesis. But it is worth mentioning that in contrast with initial data, two recent studies have failed to confirm the RELN hypermethylation, and psychotropic medication could in itself affect the reelin expression in the brain, as animal studies show (see below).
Other interesting findings probably linking reelin pathway to developmental hypotheses of schizophrenia are noted in the studies on mice that are either prenatally infected with influenza
virus or have their immune system activated artificially during pregnancy. The Cajal-Retzius cell
s in the newborns secrete significantly less reelin despite keeping their expression of calretinin
and nNos
within normal range. These data run in parallel with the findings of increased risk of schizophrenia in humans after a prenatal infection during the second trimester.
Chromosome region 7q22 that harbours the RELN gene is associated with schizophrenia, and the gene itself was associated with the disease in a large study that found the polymorphism rs7341475
to increase the risk of the disease in women, but not in men. The women that have the single-nucleotide polymorphism (SNP) are about 1.4 times more likely to get ill, according to the study. Allelic variations of RELN have also been correlated with working memory, memory and executive functioning in nuclear families where one of the members suffers from schizophrenia. The association with working memory was later replicated. In one small study, nonsynonymous polymorphism Val997Leu of the gene was associated with left and right vetricular enlargement in patients.
One study showed that patients have decreased levels of one of reelin receptors, VLDLR, in the peripheral lymphocyte
s. After six months of antipsychotic
therapy the expression went up; according to authors, peripheral VLRLR levels may serve as a reliable peripheral biomarker of schizophrenia.
Considering the role of reelin in promoting dendritogenesis, suggestions were made that the localized dendritic spine deficit observed in schizophrenia could be in part connected with the downregulation of reelin.
Reelin pathway could also be linked to schizophrenia and other psychotic disorders through its interaction with risk genes. One example is the neuronal transcription factor NPAS3
, disruption of which is linked to schizophrenia and learning disability. Knockout mice lacking NPAS3 or the similar protein NPAS1
have significantly lower levels of reelin; the precise mechanism behind this is unknown. Another example is the schizophrenia-linked gene MTHFR, with murine knockouts showing decreased levels of reelin in the cerebellum. Along the same line, it is worth noting that the gene coding for the subunit NR2B
that is presumably affected by reelin in the process of NR2B->NR2A developmental change of NMDA receptor composition, stands as one of the strongest risk gene candidates
. Another shared aspect between NR2B and RELN is that they both can be regulated by the TBR1
transcription factor.
The heterozygous
reeler mouse, which is haploinsufficient
for the RELN gene, shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder, but is considered not suitable for use as a genetic mouse model of schizophrenia.
is typical of bipolar disorder
with psychosis, but is not characteristic of patients with major depression without psychosis, which could speak of specific association of the change with psychoses. One study suggests that unlike in schizophrenia, such changes are found only in the cortex and do not affect the deeper structures in psychotic bipolar patients, as their basal ganglia were found to have the normal levels of DNMT1 and subsequently both the reelin and GAD67 levels were within the normal range.
In a genetic study conducted in 2009, preliminary evidence requiring further DNA replication
suggested that variation of the RELN gene
(SNP rs362719) may be associated with susceptibility to bipolar disorder
in women.
is a neurodevelopmental disorder that is generally believed to be caused by mutations in several locations, likely triggered by environmental factors. The role of reelin in autism is not decided yet.
Reelin was originally implicated in a study finding associations between autism and a polymorphic
GGC/CGG repeat
preceding the 5' ATG initiator codon of the RELN gene in an Italian population. Longer triplet repeats in the 5’ region were associated with an increase in autism susceptibility. However, another study of 125 multiple-incidence families and 68 single-incidence families found no significant difference between the length of the polymorphic repeats in affected and controls. Although, using a family based association test larger reelin alleles were found to be transmitted more frequently than expected to affected children. An additional study examining 158 subjects with German lineage likewise found no evidence of triplet repeat polymorphisms associated with autism. And the largest study consisting of 395 families found no association between autistic subjects and the CGG triplet repeat as well as the allele size when compared to age of first word.
Also, RELN is located at chromosome locus 7q22, which is associated with susceptibility with autism, and reduced levels of Reelin are found in autistic brains examined postmortem. More recent reports found conflicting results, with some finding an association between RELN and autism, and others not. Studies of transgenic
mice have been suggestive of an association, but not definitive.
was found to be directly correlated with the extent of granule cell
dispersion (GCD), a major feature of the disease that is noted in 45%-73% of patients. The dispersion, according to a small study, is associated with the RELN promoter hypermethylation. According to one study, prolonged seizures in a rat model of mesial temporal lobe epilepsy have led to the loss of reelin-expressing interneurons and subsequent ectopic chain migration and aberrant integration of newborn dentate granule cells. Without reelin, the chain-migrating neuroblasts failed to detach properly. Moreover, in a kainate-induced mouse epilepsy model, exogenous reelin had prevented GCD, according to one study.
(ApoE). Therefore, they are often synonymously referred to as 'ApoE receptors'. ApoE occurs in 3 common isoforms (E2, E3, E4) in the human population. ApoE4 is the primary genetic risk factor for late-onset Alzheimer's disease
. This strong genetic association has led to the proposal that ApoE receptors play a central role in the pathogenesis of Alzheimer's Disease. According to one study, reelin expression and glycosylation
patterns are altered in Alzheimer's disease
. In the cortex of the patients, reelin levels were 40% higher compared with controls, but the cerebellar levels of the protein remain normal in the same patients. This finding is in agreement with an earlier study showing the presence of Reelin associated with amyloid plaques in a transgenic AD mouse model. A large genetic study of 2008 showed that RELN gene variation is associated with an increased risk of Alzheimer's disease in women. The number of reelin-producing Cajal-Retzius cells is significantly decreased in the first cortical layer of patients. Reelin has been shown to interact with amyloid precursor protein
, and, according to one in-vitro study, is able to counteract the Aβ-induced dampening of NMDA-receptor activity. This is modulated by ApoE isoforms, which selectively alter the recycling of ApoER2 as well as AMPA and NMDA receptors.
patterns are often changed in tumours, and the RELN gene could be affected: according to one study, in the pancreatic cancer
the expression is suppressed, along with other reelin pathway components In the same study, cutting the reelin pathway in cancer cells that still expressed reelin resulted in increased motility and invasiveness. On the contrary, in prostate cancer
the RELN expression is excessive and correlates with Gleason score
. Retinoblastoma
presents another example of RELN overexpression.
indicates a possible role for RELN gene variation in otosclerosis
, an abnormal growth of bone of the middle ear
. In a statistical search for the genes that are differentially expressed in the brains of cerebral malaria-resistant versus cerebral malaria-susceptible mice, Delahaye et al. detected a significant upregulation of both RELN and DAB1
and speculated on possible protective effects of such over-expression.
The expression of reelin is controlled by a number of factors besides the sheer number of Cajal-Retzius cells. For example, TBR1
transcription factor regulates RELN along with other T-element-containing genes. On a higher level, increased maternal care was found to correlate with reelin expression in rat pups; such correlation was reported in hippocampus and in the cortex. According to one report, prolonged exposure to corticosterone
significantly decreased reelin expression in murine hippocampi, a finding possibly pertinent to the hypothetical role of corticosteroids in depression
. One small postmortem study has found increased methylation of RELN gene in the neocortex of persons past their puberty compared with those that had yet to enter the period of maturation.
According to the epigenetic hypothesis, drugs that shift the balance in favour of demethylation have a potential to alleviate the proposed methylation-caused downregulation of RELN and GAD67. In one study, clozapine and sulpiride but not haloperidol and olanzapine were shown to increase the demethylation of both genes in mice pretreated with l-methionine. Valproic acid, a histone deacetylase inhibitor, when taken in combination with antipsychotics, is proposed to have some benefits. But there are studies conflicting the main premise of the epigenetic hypothesis, and a study by Fatemi et al. shows no increase in RELN expression by valproic acid; that indicates the need for further investigation.
Fatemi et al. conducted the study in which RELN mRNA and reelin protein levels were measured in rat prefrontal cortex following a 21-day of intraperitoneal injection
s of the following drugs:
In 2009, Fatemi et al. published the more detailed work on rats using the same medication. Here, cortical expression of several participants (VLDLR, DAB1
, GSK3B
) of the signaling chain was measured besides reelin itself, and also the expression of GAD65 and GAD67.
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates the synaptic plasticity
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...
by enhancing the induction and maintenance of long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
. It also stimulates dendrite and dendritic spine
Dendritic spine
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...
development and regulates the continuing migration of neuroblast
Neuroblast
A neuroblast is a dividing cell that will develop into neurons or glia. The characterisation of neuroblasts and their development in Drosophila melanogaster was widely achieved by Chris Doe, Corey Goodman and Mike Bate. In humans, neuroblasts produced by stem cells in the adult subventricular zone...
s generated in adult neurogenesis sites like subventricular
Subventricular zone
The subventricular zone is a paired brain structure situated throughout the lateral walls of the lateral ventricles. It has been associated with having four distinct layers of variable thickness and cell density, as well as cellular composition....
and subgranular zone
Subgranular zone
The subgranular zone is a brain region in the hippocampus where adult neurogenesis occurs. It is one of the two major sites of adult neurogenesis in the brain, along with the subventricular zone .- Structure :...
s. It is found not only in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, but also in the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, and other body organs and tissues.
Reelin has been suggested to be implicated in pathogenesis of several brain diseases. The expression of the protein has been found to be significantly lower in schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and psychotic bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
, but the cause of this observation remains uncertain as studies show that psychotropic medication itself affects reelin expression. Moreover, the epigenetic hypothesis aimed at explaining the changed levels has received some contradictory evidence. Total lack of reelin causes a form of lissencephaly
Lissencephaly
Lissencephaly, which literally means smooth brain, is a rare brain formation disorder caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a lack of development of brain folds and grooves . It is a form of cephalic disorder...
. Reelin may also play a role in Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, temporal lobe epilepsy
Temporal lobe epilepsy
Temporal lobe epilepsy a.k.a. Psychomotor epilepsy, is a form of focal epilepsy, a chronic neurological condition characterized by recurrent seizures. Over 40 types of epilepsies are known. They fall into two main categories: partial-onset epilepsies and generalized-onset epilepsies...
and autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
.
Reelin's name comes from the abnormal reeling gait
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...
of reeler
Reeler
A reeler is a mouse mutant, so named because of its characteristic "reeling" gait. This is caused by profound hypoplasia of the mouse's cerebellum, in which the normal cerebellar folia are missing. The mutation is autosomal and recessive....
mice, which were later found to have a deficiency of this brain protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
and were homozygous
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
for mutation of the RELN gene.
The primary phenotype associated with loss of reelin function is a failure of neuronal positioning throughout the developing central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS). The mice heterozygous
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
for the reelin gene, while having little neuroanatomical defects, display the endophenotypic
Endophenotype
Endophenotype is a psychiatric concept and a special kind of biomarker. The purpose of the concept is to divide behavioral symptoms into more stable phenotypes with a clear genetic connection...
traits linked to psychotic disorders.
Discovery
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. Useful spontaneous mutations were first identified by scientists who were interested in motor behavior, and it proved relatively easy to screen littermates for mice that showed difficulties moving around the cage. A number of such mice were found and given descriptive names such as reeler, weaver, lurcher, nervous, and staggerer.
The "reeler
Reeler
A reeler is a mouse mutant, so named because of its characteristic "reeling" gait. This is caused by profound hypoplasia of the mouse's cerebellum, in which the normal cerebellar folia are missing. The mutation is autosomal and recessive....
" mouse was described for the first time in 1951 by D.S.Falconer
Douglas Scott Falconer
Douglas Scott Falconer FRS FRSE was a British geneticist known for his work in quantitative genetics. Falconer's book Introduction to quantitative genetics was written in 1960 and became a valuable reference for generations of scientists. Its latest edition dates back to 1996 and is coauthored by...
in Edinburgh University as a spontaneous variant arising in a colony of mice maintained by geneticist Charlotte Auerbach
Charlotte Auerbach
Charlotte Auerbach FRSE FRS was a German zoologist and geneticist.Born in Germany, she fled to Scotland because of anti-Semitism. She became well known after 1942 when she, with A. J. Clark and J. M. Robson, discovered that mustard gas could cause mutations in fruit flies...
. Histopathological
Histopathology
Histopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...
studies in the 1960s revealed that the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
of reeler mice is dramatically decreased in size while the normal laminar organization found in several brain regions is disrupted. The 1970s brought the discovery of cellular layers inversion in the mice neocortex, which attracted more attention to the reeler mutation.
In 1994, a new allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
of reeler was obtained by means of insertional mutagenesis
Mutagenesis
Mutagenesis is a process by which the genetic information of an organism is changed in a stable manner, resulting in a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures...
. This provided the first molecular marker of the locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
, permitting the RELN gene to be mapped to chromosome 7q22 and subsequently cloned and identified. Japanese scientists at Kochi Medical School successfully raised antibodies against normal brain extracts in reeler mice, later these antibodies were found to be specific monoclonal antibodies
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
for reelin, and were termed CR-50 (Cajal-Retzius marker 50). They noted that CR-50 reacted specifically with Cajal-Retzius neurons
Cajal-Retzius cell
The term Cajal–Retzius cell is applied to reelin-producing neurons of the human embryonic marginal zone which display, as a salient feature, radial ascending processes that contact the pial surface, and a horizontal axon plexus located in the deep marginal zone...
, whose functional role was unknown until then.
The Reelin receptors, apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), were discovered by Trommsdorff, Herz and colleagues, who initially found that the cytosolic adaptor protein Dab1 interacts with the cytoplasmic domain of LDL receptor family members. They then went on to show that the double knockout
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
mice for ApoER2 and VLDLR, which both interact with Dab1, had cortical layering defects similar to those in reeler.
The downstream
Upstream and downstream (transduction)
In molecular biology, the terms upstream and downstream can refer to the temporal and mechanistic order of cellular and molecular events. For example, in signal transduction, the second messenger acts downstream to activation of cell membrane receptors. The other way around, activation of cell...
pathway
Neural pathway
A neural pathway, neural tract, or neural face, connects one part of the nervous system with another and usually consists of bundles of elongated, myelin-insulated neurons, known collectively as white matter...
of reelin was further clarified with the help of other mutant mice, including yotari
Yotari
The yotari mouse is an autosomal recessive mutant. It has a mutated disabled homolog 1 gene. This mutant mouse is recognized by unstable gait and tremor and by early deaths around the time of weaning. The cytoarchitectures of cerebellar and cerebral cortices and hippocampal formation of the...
and scrambler
Scrambler mouse
Scrambler is a spontaneous mouse mutant lacking a functional DAB1 gene, resulting in a phenotype resembling that seen in the reeler mouse. The strain was first described by Sweet et al in 1996.-Neuroanatomical abnormalities:...
. These mutants have phenotypes similar to that of reeler mice, but without mutation in reelin. It was then demonstrated that the mouse disabled homologue 1 (Dab1
DAB1
The Disabled-1 gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway...
) gene is responsible for the phenotypes of these mutant mice, as Dab1 protein was absent (yotari) or only barely detectable (scrambler) in these mutants. Targeted disruption of Dab1 also caused a phenotype similar to that of reeler. Pinpointing the DAB1
DAB1
The Disabled-1 gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway...
as a pivotal regulator of the reelin signaling cascade started the tedious process of deciphering its complex interactions.
There followed a series of speculative reports linking reelin's genetic variation and interactions to schizophrenia, Alzheimer's disease, autism and other highly complex dysfunctions. These and other discoveries, coupled with the perspective of unraveling the evolutionary changes that allowed for the creation of human brain, highly intensified the research. As of 2008, some 13 years after the gene coding the protein was discovered, hundreds of scientific articles address the multiple aspects of its structure and functioning.
Tissue distribution and secretion
Synaptic vesicle
In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
s and is secreted via constitutive secretory pathway
Secretory pathway
The secretory pathway is a series of steps a cell uses to move proteins out of the cell; a process known as secretion. The path of a protein destined for secretion has its origins in the rough endoplasmic reticulum, a membrane-bound compartment in the cell...
, being stored in Golgi
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
secretory vesicles. Reelin's release rate is not regulated by depolarization
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
, but strictly depends on its synthesis rate. This relationship is similar to that reported for the secretion of other extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
proteins.
During the brain development, reelin is secreted in the cortex and hippocampus by the so-called Cajal-Retzius cell
Cajal-Retzius cell
The term Cajal–Retzius cell is applied to reelin-producing neurons of the human embryonic marginal zone which display, as a salient feature, radial ascending processes that contact the pial surface, and a horizontal axon plexus located in the deep marginal zone...
s, Cajal cells, and Retzius cells. Reelin-expressing cells in the prenatal and early postnatal brain are predominantly found in the marginal zone (MZ) of the cortex and in the temporary subpial granular layer (SGL), which is manifested to the highest extent in human, and in the hippocampal stratum lacunosum-moleculare and the upper marginal layer of the dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...
.
In the developing cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
, reelin is expressed first in the external granule cell
Granule cell
In neuroscience, granule cells refer to tiny neurons that are around 10 micrometres in diameter. Granule cells are found within the granular layer of the cerebellum , the dentate gyrus of the...
layer (EGL), before the granule cell migration to the internal granule cell layer (IGL) takes place.
Having peaked just after the birth, the synthesis of reelin subsequently goes down sharply, becoming more diffuse compared with the distinctly laminar expression in the developing brain. In the adult brain, reelin is expressed by GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
-ergic interneuron
Interneuron
An interneuron is a multipolar neuron which connects afferent neurons and efferent neurons in neural pathways...
s of the cortex and glutamatergic cerebellar neurons, and by the few extant Cajal-Retzius cells. Among GABAergic interneurons, reelin seems to be detected predominantly in those expressing calretinin
Calretinin
Calretinin also known as 29 kDa calbindin is a vitamin D-dependent calcium-binding protein involved in calcium signaling. In humans, the calretinin protein is encoded by the CALB2 gene.- Function :...
and calbindin
Calbindin
Calbindin refers to several calcium-binding proteins. They were originally described as vitamin D-dependent calcium-binding proteins in the intestine and kidney in the chick and mammals...
, like bitufted, horizontal, and Martinotti cell
Martinotti cell
Martinotti cells are small multipolar neurons with short branching dendrites. They are scattered throughout various layers of the cerebral cortex, sending their axons up to the cortical layer I where they form axonal arborization...
s, but not parvalbumin
Parvalbumin
Parvalbumin is a calcium-binding albumin protein with low molecular weight .It has three EF hand motifs and is structurally related to calmodulin and troponin C...
-expressing cells, like chandelier
Chandelier cell
Chandelier neurons or chandelier cells are a subset of GABA-ergic cortical interneurons. They are described as parvalbumin-containing and fast-spiking to distinguish them from other subtypes of GABAergic neurons. The name comes from the specific shape of their axon arbors, with the terminals...
or basket neurons. In the white matter, a minute proportion of interstitial neurons has also been found to stain positive for reelin expression.
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, pituitary pars intermedia
Pars intermedia
Pars intermedia is the boundary between the anterior and posterior lobes of the pituitary. It contains three types of cells - basophils, chromophobes, and colloid-filled cysts. The cysts are the remainder of Rathke’s pouch....
, and adrenal chromaffin cell
Chromaffin cell
Chromaffin cells are neuroendocrine cells found in the medulla of the adrenal gland and in other ganglia of the sympathetic nervous system. They are modified post-synaptic sympathetic neurons that receive sympathetic input...
s. In the liver, reelin is localized in hepatic stellate cell
Hepatic stellate cell
Hepatic stellate cells , also known as perisinusoidal cells or Ito cells , are pericytes found in the perisinusoidal space of the liver also known as the space of Disse...
s. The expression of reelin increases when the liver is damaged, and returns to normal following its repair.
In the eyes, reelin is secreted by retinal ganglion cells and is also found in the endothelial layer of the cornea
Corneal endothelium
The corneal endothelium is a single layer of cells on the inner surface of the cornea. It faces the chamber formed between the cornea and the iris....
. Just as in the liver, its expression increases after an injury has taken place.
The protein is also produced by the odontoblast
Odontoblast
In vertebrates, an odontoblast is a biological cell of neural crest origin that is part of the outer surface of the dental pulp, and whose biological function is dentinogenesis, which is the creation of dentin, the substance under the tooth enamel....
s, which are cells at the margins of the dental pulp. Reelin is found here both during odontogenesis and in the mature tooth. Some authors suggest that odontoblasts play an additional role as sensory cells able to transduce
Transduction (physiology)
In physiology, transduction is the conversion of a stimulus from one form to another.Transduction in the nervous system typically refers to stimulus alerting events wherein a mechanical/physical/etc stimulus is converted into an action potential which is transmitted along axons towards the central...
pain signals to the nerve endings. According to the hypothesis, reelin participates in the process by enhancing the contact between odontoblasts and the nerve terminals.
Structure
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
composed of 3461 amino acids with a relative molecular mass of 388 kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
. It also has serine protease
Serine protease
Serine proteases are enzymes that cleave peptide bonds in proteins, in which serine serves as the nucleophilic amino acid at the active site.They are found ubiquitously in both eukaryotes and prokaryotes...
activity. Murine RELN gene consists of 65 exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s spanning approximately 450 kb
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
. One exon, coding for only two amino acids near the protein's C-terminus, undergoes alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
, but the exact functional impact of this is unknown. Two transcription initiation sites and two polyadenylation sites are identified in the gene structure.
The reelin protein starts with a signaling peptide 27 amino acids in length, followed by a region bearing similarity to F-spondin
Spondin 1
Spondin-1 is a protein that in humans is encoded by the SPON1 gene. The protein contains 807 aminoacids and is structurally composed of six thrombospondin domains, one reelin domain, and one spondin domain.-Further reading:...
(the reeler domain
Reeler domain
Reeler domain is a protein domain.Extracellular matrix proteins play an important role in early cortical development, specifically in the formation of neural connections and in controlling the cyto-architecture of the central nervous system...
), marked as "SP" on the scheme, and by a region unique to reelin, marked as "H". Next comes 8 repeats of 300-350 amino acids. These are called reelin repeats and have an epidermal growth factor
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
motif at their center, dividing each repeat into two subrepeats, A (the BNR/Asp-box repeat
BNR/Asp-box repeat
BNR/Asp-box repeat is a repetitive sequence of amino acids contained in some proteins.Members of this family contain multiple BNR repeats or Asp-boxes. The repeats are short, however the repeats are never found closer than 40 residues together suggesting that the repeat is structurally longer...
) and B (the EGF-like domain
EGF-like domain
EGF-like domain is an evolutionary conserved protein domain, of about thirty to forty amino-acid residues long, which was found in a large number of mostly animal proteins. All these repeats are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted...
). Despite this interruption, the two subdomains make direct contact, resulting in a compact overall structure.
The final reelin domain contains a highly basic and short C-terminal region (CTR, marked "+") with a length of 32 amino acids. This region is highly conserved, being 100% identical in all investigated mammals. It was thought that CTR is necessary for reelin secretion, because the Orleans reeler
Reeler
A reeler is a mouse mutant, so named because of its characteristic "reeling" gait. This is caused by profound hypoplasia of the mouse's cerebellum, in which the normal cerebellar folia are missing. The mutation is autosomal and recessive....
mutation, which lacks a part of 8th repeat and the whole CTR, is unable to secrete the misshaped protein, leading to its concentration in cytoplasm. However, other studies have shown that the CTR is not essential for secretion itself, but mutants lacking the CTR were much less efficient in activating downstream signaling events.
Reelin is cleaved in vivo at two sites located after domains 2 and 6 – approximately between repeats 2 and 3 and between repeats 6 and 7, resulting in the production of three fragments. This splitting does not decrease the protein's activity, as constructs made of the predicted central fragments (repeats 3–6) bind to lipoprotein receptors, trigger Dab1
DAB1
The Disabled-1 gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway...
phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
and mimic functions of reelin during cortical plate development. Moreover, the processing of reelin by embryonic neurons may be necessary for proper corticogenesis.
Function
During development
A number of non-nervous tissues and organs express reelin during development, with the expression sharply going down after organs have been formed. The role of the protein here is largely unexplored, because the knockout mice show no major pathology in these organs. Reelin's role in the growing central nervous system has been extensively characterized. It promotes the differentiation of progenitor cells into radial gliaRadial glia
Radial glial cells are a pivotal cell type in the developing central nervous system involved in key developmental processes, from patterning and neuronal migration to their recently discovered role as precursors during neurogenesis. They arise early in development from neuroepithelial cells...
and affects the orientation of its fibers, which serve as the guides for the migrating neuroblasts. The position of reelin-secreting cell layer is important, because the fibers orient themselves in the direction of its higher concentration. For example, reelin regulates the development of layer-specific connections in hippocampus and entorhinal cortex.
Reeler
A reeler is a mouse mutant, so named because of its characteristic "reeling" gait. This is caused by profound hypoplasia of the mouse's cerebellum, in which the normal cerebellar folia are missing. The mutation is autosomal and recessive....
mouse, the order of cortical layering becomes roughly inverted, with younger neurons finding themselves to be unable to pass the settled layers. Subplate neurons fail to stop and invade the upper most layer, creating the so-called superplate in which they mix with Cajal-Retzius cell
Cajal-Retzius cell
The term Cajal–Retzius cell is applied to reelin-producing neurons of the human embryonic marginal zone which display, as a salient feature, radial ascending processes that contact the pial surface, and a horizontal axon plexus located in the deep marginal zone...
s and some cells normally destined for the second layer.
Reelin may also ensure correct neuronal positioning in the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
: according to one study, location and level of its expression affects the movement of sympathetic preganglionic neurons.
The protein is thought to act on migrating neuronal precursors and thus controls correct cell positioning in the cortex and other brain structures. The proposed role is one of a dissociation signal for neuronal groups, allowing them to separate and go from tangential chain-migration to radial individual migration. Dissociation detaches migrating neurons from the glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
s that are acting as their guides, converting them into individual cells that can strike out alone to find their final position.
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
configuration, increasing mobility of NR2B-containing receptors and thus decreasing the time they spend at the synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
. It has been hypothesized that this may be a part of the mechanism behind the "NR2B-NR2A switch" that is observed in the brain during its postnatal development. Ongoing reelin secretion by GABAergic hippocampal neurons is necessary to keep NR2B-containing NMDA receptors at a low level.
In adults
In the adult nervous system, reelin plays an eminent role at the two most active neurogenesis sites, the subventricular zone and the dentate gyrus. In some species, the neuroblasts from the subventricular zone migrate in chains in the rostral migratory streamRostral migratory stream
The rostral migratory stream is a pathway found in the brain of some animals along which neuronal precursors that originated in the subventricular zone of the brain migrate to reach the main olfactory bulb . This pathway has been studied in the rodent, rabbit, and both the squirrel and rheusus...
(RMS) to reach the olfactory bulb, where reelin dissociates them into individual cells that are able to migrate further individually. They change their mode of migration from tangential to radial, and begin using the radial glia fibers as their guides. There are studies showing that along the RMS itself the two receptors, ApoER2 and VLDLR, and their intracellular adapter DAB1
DAB1
The Disabled-1 gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway...
function independently of Reelin, most likely by the influence of a newly proposed ligand, thrombospondin-1. In the adult dentate gyrus, reelin provides guidance cues for new neurons that are constantly arriving to the granule cell layer from subgranular zone, keeping the layer compact.
Reelin also plays an important role in the adult brain by modulating cortical pyramidal neuron dendritic spine
Dendritic spine
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...
expression density, the branching of dendrite
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...
s, and the expression of long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
as its secretion is continued diffusely by the GABAegric cortical interneurons those origin is traced to the medial ganglionic eminence
Ganglionic eminence
In neuroanatomy and neuroembryology, a ganglionic eminence is a transitory brain structure present in the embryonic and fetal stages of brain development. The eminences are found in the ventral part of the telencephalon, where they form bulges in the ventricles. These bulges develop into the basal...
.
In the adult organism the non-neural expression is much less widespread, but goes up sharply when some organs are injured. The exact function of reelin upregulation following an injury is still being researched.
Evolutionary significance
Amniote
The amniotes are a group of tetrapods that have a terrestrially adapted egg. They include synapsids and sauropsids , as well as their fossil ancestors. Amniote embryos, whether laid as eggs or carried by the female, are protected and aided by several extensive membranes...
s into multiple-layered cortex of contemporary mammals. Research shows that reelin expression goes up as the cortex becomes more complex, reaching the maximum in the human brain in which the reelin-secreting Cajal-Retzius cells have significantly more complex axonal arbour. Reelin is present in the telencephalon of all the vertebrates studied so far, but the pattern of expression differs widely. For example, zebrafish have no Cajal-Retzius cells at all; instead, the protein is being secreted by other neurons. These cells do not form a dedicated layer in amphibians, and radial migration in their brains is very weak.
As the cortex becomes more complex and convoluted, migration along the radial glia fibers becomes more important for the proper lamination. The emergence of a distinct reelin-secreting layer is thought to play an important role in this evolution. There are conflicting data concerning the importance of this layer, and these are explained in the literature either by the existence of an additional signaling positional mechanism that interacts with the reelin cascade, or by the assumption that mice that are used in such experiments have redundant secretion of reelin compared with more localized synthesis in the human brain.
Cajal-Retzius cells, most of which disappear around the time of birth, coexpress reelin with the HAR1 gene that is thought to have undergone the most significant evolutionary change in humans compared with chimpanzee, being the most "evolutionary accelerated" of the genes from the human accelerated regions
Human accelerated regions
Human accelerated regions , first described in August 2006, are a set of 49 segments of the human genome which are conserved throughout vertebrate evolution but are strikingly different in humans. They are named HAR1 through HAR49 according to their degree of difference between humans and chimpanzees...
. There is also evidence of that variants in the DAB1 gene have been included in a recent selective sweep in Chinese populations.
Mechanism of action
Receptors
Reelin's control of cell-cell interactions is thought to be mediated by binding of reelin to the two members of low density lipoprotein receptor gene familyLow density lipoprotein receptor gene family
The low density lipoprotein receptor gene family code for a class of structurally closely related cell surface receptors that fulfill diverse biological functions in different organs, tissues, and cell types. The role that is most commonly associated with this evolutionarily ancient family is...
: VLDLR
VLDL receptor
The very-low-density-lipoprotein receptor is a lipoprotein receptor that shows considerable similarity to the low-density-lipoprotein receptor...
and the ApoER2
Low density lipoprotein receptor-related protein 8
Low-density lipoprotein receptor-related protein 8 is a protein that in humans is encoded by the LRP8 gene.Low density lipoprotein receptor-related protein 8, or LRP8 is a member of the LDL receptor family that plays a role in endocytosis and signal transduction...
. The two main reelin receptors seem to have slightly different roles: VLDLR conducts the stop signal, while ApoER2 is essential for the migration of late-born neocortical neurons. It also has been shown that the N-terminal region of reelin, a site distinct from the region of reelin shown to associate with VLDLR/ApoER2 binds to the alpha-3-beta-1 integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
receptor. The proposal that the protocadherin
Cadherin
Cadherins are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. They are dependent on calcium ions to function, hence their name.The cadherin superfamily includes cadherins, protocadherins, desmogleins, and...
CNR1 behaves as a Reelin receptor has been disproven.
As members of lipoprotein receptor superfamily, both VLDLR and ApoER2 have in their structure an internalization domain called NPxY motif
Structural motif
In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a supersecondary structure, which appears also in a variety of other molecules...
. After binding to the receptors reelin is internalized by endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
, and the N-terminal fragment of the protein is re-secreted. This fragment may serve postnatally to prevent apical dendrites of cortical layer II/III pyramidal neurons from overgrowth, acting via a pathway independent of canonical reelin receptors.
Reelin receptors are present on both neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s and glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
s. Furthermore radial glia
Radial glia
Radial glial cells are a pivotal cell type in the developing central nervous system involved in key developmental processes, from patterning and neuronal migration to their recently discovered role as precursors during neurogenesis. They arise early in development from neuroepithelial cells...
express the same amount of ApoER2
Low density lipoprotein receptor-related protein 8
Low-density lipoprotein receptor-related protein 8 is a protein that in humans is encoded by the LRP8 gene.Low density lipoprotein receptor-related protein 8, or LRP8 is a member of the LDL receptor family that plays a role in endocytosis and signal transduction...
but being ten times less rich in VLDLR
VLDL receptor
The very-low-density-lipoprotein receptor is a lipoprotein receptor that shows considerable similarity to the low-density-lipoprotein receptor...
. beta-1 integrin receptors
CD29
Integrin beta-1 is a protein that in humans is encoded by the ITGB1 gene. CD29 is an integrin unit associated with very late antigen receptors. It is known to conjoin with alpha-3 subunit to create α3β1 complex that reacts to such molecules as netrin-1 and reelin.Integrins are heterodimeric...
on glial cells play more important role in neuronal layering than the same receptors on the migrating neuroblasts.
Reelin-dependent strengthening of long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
is caused by ApoER2 interaction with NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
. This interaction happens when ApoER2 has a region coded by exon 19. ApoER2 gene is alternatively spliced, with the exon 19-containing variant more actively produced during periods of activity. According to one study, the hippocampal reelin expression rapidly goes up when there is need to store a memory, as demethylase
Demethylase
Demethylases are enzymes that remove methyl groups from proteins and other substances. They are used in a variety of processes, such as in chemotaxis signal transduction.-Hydrolytic demethylation:A good example of a demethylase is the activated Demethylases are enzymes that remove methyl (CH3-)...
s open up the RELN gene. The activation of dendrite growth by reelin is apparently conducted through Src
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
family kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
s and is dependent upon the expression of Crk
CRK (gene)
Adapter molecule crk also known as proto-oncogene c-Crk or p38 is a protein that in humans is encoded by the CRK gene.- Function :...
family proteins, consistent with the interaction of Crk and CrkL with tyrosine-phosphorylated Dab1. Moreover, a Cre-loxP recombination
Cre-Lox recombination
Cre-Lox recombination is a special type of site-specific recombination developed by Dr. Brian Sauer initially for use in activating gene expression in mammalian cell lines and transgenic mice . Subsequently, the laboratory of Dr...
mouse model that lacks Crk
CRK (gene)
Adapter molecule crk also known as proto-oncogene c-Crk or p38 is a protein that in humans is encoded by the CRK gene.- Function :...
and CrkL
CRKL
Crk-like protein is a protein that in humans is encoded by the CRKL gene.CrkL together with Crk participates in the Reelin signaling cascade downstream of DAB1.-Interactions:...
in most neurons was reported to have the reeler
Reeler
A reeler is a mouse mutant, so named because of its characteristic "reeling" gait. This is caused by profound hypoplasia of the mouse's cerebellum, in which the normal cerebellar folia are missing. The mutation is autosomal and recessive....
phenotype, indicating that Crk/CrkL lie between DAB1
DAB1
The Disabled-1 gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway...
and Akt
AKT1
RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. Multiple alternatively spliced transcript variants have been found for this gene.- Function :...
in the reelin signaling chain.
Signaling cascades
Reelin activates the signaling cascade of Notch-1NOTCH1
Notch homolog 1, translocation-associated , also known as NOTCH1, is a human gene encoding a single-pass transmembrane receptor.A deficiency can be associated with bicuspid aortic valve....
, inducing the expression of FABP7
FABP7
Fatty acid binding protein 7, brain , is a human gene.FABP7 is expressed, during development, in radial glia by the activation of Notch receptors...
and prompting progenitor cells to assume radial glia
Radial glia
Radial glial cells are a pivotal cell type in the developing central nervous system involved in key developmental processes, from patterning and neuronal migration to their recently discovered role as precursors during neurogenesis. They arise early in development from neuroepithelial cells...
l phenotype. In addition, corticogenesis in vivo is highly dependent upon reelin being processed by embrionic neurons, which are thought to secrete some as yet unidentified metalloproteinase
Metalloproteinase
Metalloproteinases constitute a family of enzymes from the group of proteases, classified by the nature of the most prominent functional group in their active site. These are proteolytic enzymes whose catalytic mechanism involves a metal. Most metalloproteases are zinc-dependent, but some use...
s that free the central signal-competent part of the protein. Some other unknown proteolytic mechanisms may also play a role. It is supposed that full-sized reelin sticks to the extracellular matrix fibers on the higher levels, and the central fragments, as they are being freed up by the breaking up of reelin, are able to permeate into the lower levels. It is possible that as neuroblast
Neuroblast
A neuroblast is a dividing cell that will develop into neurons or glia. The characterisation of neuroblasts and their development in Drosophila melanogaster was widely achieved by Chris Doe, Corey Goodman and Mike Bate. In humans, neuroblasts produced by stem cells in the adult subventricular zone...
s reach the higher levels they stop their migration either because of the heightened combined expression of all forms of reelin, or due to the peculiar mode of action of the full-sized reelin molecules and its homodimers.
The intracellular adaptor DAB1
DAB1
The Disabled-1 gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway...
binds to the VLDLR and ApoER2 through an NPxY motif and is involved in transmission of Reelin signals through these lipoprotein receptors. It becomes phosphorylated by Src
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
and Fyn
FYN
Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth...
kinases and apparently stimulates the actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
cytoskeleton to change its shape, affecting the proportion of integrin receptors on the cell surface, which leads to the change in adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
. Phosphorylation of DAB1 leads to its ubiquitination and subsequent degradation, and this explains the hightened levels of DAB1 in the absence of reelin. Such negative feedback
Negative feedback
Negative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
is thought to be important for proper cortical lamination. Activated by two antibodies, VLDLR and ApoER2 cause DAB1 phosphorylation but seemingly without the subsequent degradation and without rescuing the reeler
Reeler
A reeler is a mouse mutant, so named because of its characteristic "reeling" gait. This is caused by profound hypoplasia of the mouse's cerebellum, in which the normal cerebellar folia are missing. The mutation is autosomal and recessive....
phenotype, and this may indicate that a part of the signal is conducted independently of DAB1.
Lissencephaly
Lissencephaly, which literally means smooth brain, is a rare brain formation disorder caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a lack of development of brain folds and grooves . It is a form of cephalic disorder...
and accordingly called LIS1 (PAFAH1B1
PAFAH1B1
Platelet-activating factor acetylhydrolase IB subunit alpha is an enzyme that in humans is encoded by the PAFAH1B1 gene.According to one study, PAFAH1B1 interacts with VLDLR receptor activated by reelin.-Genomics:...
), was shown to interact with the intracellular segment of VLDLR, thus reacting to the activation of reelin pathway.
Complexes
Reelin molecules have been shown to form a large protein complex, a disulfide-linkedDisulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
homodimer. If the homodimer fails to form, efficient tyrosine phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of DAB1 in vitro fails. Moreover, the two main receptors of reelin are able to form clusters that most probably play a major role in the signaling, causing the intracellular adaptor DAB1 to dimerize or oligomerize in its turn. Such clustering has been shown in the study to activate the signaling chain even in the absence of Reelin itself. In addition, reelin itself can cut the peptide bonds holding other proteins together, being a serine protease
Serine protease
Serine proteases are enzymes that cleave peptide bonds in proteins, in which serine serves as the nucleophilic amino acid at the active site.They are found ubiquitously in both eukaryotes and prokaryotes...
, and this may affect the cellular adhesion and migration processes. Reelin signaling leads to phosphorylation of actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
-interacting protein cofilin 1
Cofilin 1
Cofilin 1 , also known as CFL1, is a human gene, part of the ADF/cofilin family.Cofilin is a widely distributed intracellular actin-modulating protein that binds and depolymerizes filamentous F-actin and inhibits the polymerization of monomeric G-actin in a pH-dependent manner...
at ser3; this may stabilize the actin cytoskeleton and anchor the leading processes of migrating neuroblasts, preventing their further growth.
Interaction with Cdk5
Cyclin-dependent kinase 5Cyclin-dependent kinase 5
Cell division protein kinase 5 is an enzyme that in humans is encoded by the CDK5 gene. The protein encoded by this gene is part of the cyclin-dependent kinase family.-Physiological Role:...
(Cdk5), a major regulator of neuronal migration and positioning, is known to phosphorylate DAB1
DAB1
The Disabled-1 gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway...
and other cytosolic targets of reelin signaling, such as Tau
Tau protein
Tau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes...
, which could be activated also via reelin-induced deactivation of GSK3B
GSK3B
Glycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that in humans is encoded by the GSK3B gene.- Function :Glycogen synthase kinase-3 is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase. Two isoforms,...
, and NUDEL
NDEL1
Nuclear distribution protein nudE-like 1 is a protein that in humans is encoded by the NDEL1 gene.This gene encodes a thiol-activated oligopeptidase that is phosphorylated in M phase of the cell cycle...
, associated with Lis1
PAFAH1B1
Platelet-activating factor acetylhydrolase IB subunit alpha is an enzyme that in humans is encoded by the PAFAH1B1 gene.According to one study, PAFAH1B1 interacts with VLDLR receptor activated by reelin.-Genomics:...
, one of the DAB1 targets. LTP
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
induction by reelin in hippocampal slices fails in p35
CDK5R1
Cyclin-dependent kinase 5 activator 1 is an enzyme that in humans is encoded by the CDK5R1 gene.-Interactions:CDK5R1 has been shown to interact with CDK5RAP2, Beta-catenin, Cyclin-dependent kinase 5, Amphiphysin, Protein SET, CAMK2A, Actinin, alpha 1 and PCTK1.-Further reading:...
knockouts. P35 is a key Cdk5 activator, and double p35/Dab1, p35/RELN, p35/ApoER2, p35/VLDLR knockouts display increased neuronal migration deficits, indicating a synergistic action of reelin → ApoER2/VLDLR → DAB1 and p35/p39 → Cdk5 pathways in the normal corticogenesis.
Lissencephaly
Disruptions of the RELN gene are considered to be the cause of the rare form of lissencephalyLissencephaly
Lissencephaly, which literally means smooth brain, is a rare brain formation disorder caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a lack of development of brain folds and grooves . It is a form of cephalic disorder...
with cerebellar hypoplasia
Cerebellar hypoplasia
Cerebellar hypoplasia is a developmental disorder characterized by the incomplete or underdevelopment of the cerebellum. It may be genetic or occur sporadically. Cerebellar hypoplasia may be caused by thyroid abnormalities, environmental influences such as drugs and chemicals or viral infections or...
called Norman-Roberts syndrome
Norman-Roberts syndrome
Lissencephaly 2, more commonly called Norman-Roberts syndrome, is a rare form of lissencephaly caused by a mutation in the reelin gene. A small number of cases have been described. The syndrome was first reported by M. Norman and M. Roberts et al. in 1976.Lack of reelin prevents normal layering of...
. The mutations disrupt splicing
Splicing (genetics)
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
of the RELN mRNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
transcript, resulting in low or undetectable amounts of reelin protein. The phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
in these patients was characterized by hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, and developmental delay, with lack of unsupported sitting and profound mental retardation with little or no language development. Seizures and congenital lymphedema
Congenital lymphedema
Congenital lymphedema is a blockage of fluid in the developing fetal lymphatic system. It is diagnosed by a nuchal scan. Presence of this condition is also associated with congenital heart defect....
are also present. A novel chromosomal translocation
Chromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
causing the syndrome was described in 2007. The mutations affecting reelin in human are usually associated with consanguineous marriage
Consanguinity
Consanguinity refers to the property of being from the same kinship as another person. In that respect, consanguinity is the quality of being descended from the same ancestor as another person...
.
Schizophrenia
Reduced expression of reelin and its mRNAMessenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
levels in the brains of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
sufferers had been reported in 1998 and 2000 and independently confirmed in the postmortem studies of hippocampus, cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
, basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
, and in the cortex studies. The reduction may reach up to 50% in some brain regions and is coupled with reduced expression of GAD-67 enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
, which catalyses the transition of glutamate to GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
. Blood levels
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
of reelin and its isoforms are also altered in schizophrenia, along with mood disorder
Mood disorder
Mood disorder is the term designating a group of diagnoses in the Diagnostic and Statistical Manual of Mental Disorders classification system where a disturbance in the person's mood is hypothesized to be the main underlying feature...
s, according to one study. Reduced reelin mRNA prefrontal expression in schizophrenia was found to be the most statistically relevant disturbance found in the multicenter study conducted in 14 separate laboratories in 2001 by Stanley Foundation Neuropathology Consortium.
Epigenetic
Epigenetics
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- -genetics...
hypermethylation of DNA in schizophrenia patients is proposed as a cause of the reduction, in agreement with the observations dating from the 1960s that administration of methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
to schizophrenic patients results in a profound exacerbation of schizophrenia symptoms in sixty to seventy percent of patients. The proposed mechanism is a part of the "epigenetic hypothesis for schizophrenia pathophysiology" formulated by a group of scientists in 2008 (D. Grayson; A. Guidotti; E. Costa
Erminio Costa
Erminio Costa was a neuroscientist. His research interests covered brain serotonergic activity in health and disease, benzodiazepine-GABA interactions, benzodiazepine action at GABAA receptors, and GABAergic dysfunction and changes in the expression of reelin and GAD67 in schizophrenia...
). A postmortem study comparing a DNA methyltransferase
DNA methyltransferase
In biochemistry, the DNA methyltransferase family of enzymescatalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions...
(DNMT1) and Reelin mRNA expression in cortical layers I and V of schizophrenic patients and normal controls demonstrated that in the layer V both DNMT1 and Reelin levels were normal, while in the layer I DNMT1 was threefold higher, probably leading to the twofold decrease in the Reelin expression. There is evidence that the change is selective, and DNMT1 is overexpressed in reelin-secreting GABAegric neurons but not in their glutamatergic neighbours. Methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
inhibitors and histone deacetylase
Histone deacetylase
Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
inhibitors, such as valproic acid
Valproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
, increase reelin mRNA levels, while L-methionine treatment downregulates the phenotypic expression of reelin. One study indicated the upregulation of histone deacetylase HDAC1 in the hippocampi of patients. Histone deacetylases suppress gene promoters; hyperacetylation of hystones was shown in murine models to demethylate the promoters of both reelin and GAD67. DNMT1 inhibitors in animals have been shown to increase the expression of both reelin and GAD67, and both DNMT inhibitors and HDAC inhibitors shown in one study to activate both genes with comparable dose- and time-dependence. As one study shows, S-adenosyl methionine
S-Adenosyl methionine
S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952. It is made from adenosine triphosphate and methionine by methionine adenosyltransferase . Transmethylation, transsulfuration, and aminopropylation are the...
(SAM) concentration in patients' prefrontal cortex is twice as high as in the cortices of non-affected people. SAM, being a methyl group donor necessary for DNMT activity, could further shift epigenetic control of gene expression.
The factors mentioned above serve to corroborate the epigenetic hypothesis. But it is worth mentioning that in contrast with initial data, two recent studies have failed to confirm the RELN hypermethylation, and psychotropic medication could in itself affect the reelin expression in the brain, as animal studies show (see below).
Other interesting findings probably linking reelin pathway to developmental hypotheses of schizophrenia are noted in the studies on mice that are either prenatally infected with influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
virus or have their immune system activated artificially during pregnancy. The Cajal-Retzius cell
Cajal-Retzius cell
The term Cajal–Retzius cell is applied to reelin-producing neurons of the human embryonic marginal zone which display, as a salient feature, radial ascending processes that contact the pial surface, and a horizontal axon plexus located in the deep marginal zone...
s in the newborns secrete significantly less reelin despite keeping their expression of calretinin
Calretinin
Calretinin also known as 29 kDa calbindin is a vitamin D-dependent calcium-binding protein involved in calcium signaling. In humans, the calretinin protein is encoded by the CALB2 gene.- Function :...
and nNos
NOS1
Nitric oxide synthase 1 , also known as NOS1, is an enzyme that in humans is encoded by the NOS1 gene.- Function :Nitric oxide is a messenger molecule with diverse functions throughout the body...
within normal range. These data run in parallel with the findings of increased risk of schizophrenia in humans after a prenatal infection during the second trimester.
Chromosome region 7q22 that harbours the RELN gene is associated with schizophrenia, and the gene itself was associated with the disease in a large study that found the polymorphism rs7341475
Rs7341475
In genetics, rs7341475 is a single nucleotide polymorphism in the RELN gene that codes the reelin protein.The gene is located in the fourth intron on human chromosome 7....
to increase the risk of the disease in women, but not in men. The women that have the single-nucleotide polymorphism (SNP) are about 1.4 times more likely to get ill, according to the study. Allelic variations of RELN have also been correlated with working memory, memory and executive functioning in nuclear families where one of the members suffers from schizophrenia. The association with working memory was later replicated. In one small study, nonsynonymous polymorphism Val997Leu of the gene was associated with left and right vetricular enlargement in patients.
One study showed that patients have decreased levels of one of reelin receptors, VLDLR, in the peripheral lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s. After six months of antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
therapy the expression went up; according to authors, peripheral VLRLR levels may serve as a reliable peripheral biomarker of schizophrenia.
Considering the role of reelin in promoting dendritogenesis, suggestions were made that the localized dendritic spine deficit observed in schizophrenia could be in part connected with the downregulation of reelin.
Reelin pathway could also be linked to schizophrenia and other psychotic disorders through its interaction with risk genes. One example is the neuronal transcription factor NPAS3
NPAS3
NPAS3 or Neuronal PAS domain protein 3 is a brain-enriched transcription factor belonging to the bHLH-PAS superfamily of transcription factors, the members of which carry out diverse functions, including circadian oscillations, neurogenesis, toxin metabolism, hypoxia, and tracheal development...
, disruption of which is linked to schizophrenia and learning disability. Knockout mice lacking NPAS3 or the similar protein NPAS1
NPAS1
NPAS1 is a basic-helix-loop-helix transcription factor....
have significantly lower levels of reelin; the precise mechanism behind this is unknown. Another example is the schizophrenia-linked gene MTHFR, with murine knockouts showing decreased levels of reelin in the cerebellum. Along the same line, it is worth noting that the gene coding for the subunit NR2B
GRIN2B
Glutamate [NMDA] receptor subunit epsilon-2 also known as N-methyl D-aspartate receptor subtype 2B is a protein that in humans is encoded by the GRIN2B gene.- Function :...
that is presumably affected by reelin in the process of NR2B->NR2A developmental change of NMDA receptor composition, stands as one of the strongest risk gene candidates
Candidate gene
A candidate gene is a gene, located in a chromosome region suspected of being involved in the expression of a trait such as a disease, whose protein product suggests that it could be the gene in question...
. Another shared aspect between NR2B and RELN is that they both can be regulated by the TBR1
TBR1
T-box, brain, 1 is a protein that in humans is encoded by the TBR1 gene. This gene is also known by several other names: T-Brain 1, TBR-1, TES-56, and MGC141978. TBR1 is a member of the T-box family of transcription factors that share a common DNA-binding domain...
transcription factor.
The heterozygous
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
reeler mouse, which is haploinsufficient
Haploinsufficiency
Haploinsufficiency occurs when a diploid organism only has a single functional copy of a gene and the single functional copy of the gene does not produce enough of a gene product to bring about a wild-type condition, leading to an abnormal or diseased state...
for the RELN gene, shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder, but is considered not suitable for use as a genetic mouse model of schizophrenia.
Bipolar disorder
Decrease in RELN expression with concurrent upregulation of DNMT1DNMT1
DNA -methyltransferase 1 is an enzyme that in humans is encoded by the DNMT1 gene.-Interactions:DNMT1 has been shown to interact with Histone deacetylase 2, DMAP1, PCNA, Retinoblastoma protein, DNMT3A and DNMT3B.-Further reading:...
is typical of bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
with psychosis, but is not characteristic of patients with major depression without psychosis, which could speak of specific association of the change with psychoses. One study suggests that unlike in schizophrenia, such changes are found only in the cortex and do not affect the deeper structures in psychotic bipolar patients, as their basal ganglia were found to have the normal levels of DNMT1 and subsequently both the reelin and GAD67 levels were within the normal range.
In a genetic study conducted in 2009, preliminary evidence requiring further DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
suggested that variation of the RELN gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
(SNP rs362719) may be associated with susceptibility to bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
in women.
Autism
AutismAutism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
is a neurodevelopmental disorder that is generally believed to be caused by mutations in several locations, likely triggered by environmental factors. The role of reelin in autism is not decided yet.
Reelin was originally implicated in a study finding associations between autism and a polymorphic
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
GGC/CGG repeat
Repeated sequence (DNA)
In the study of DNA sequences, one can distinguish two main types of repeated sequence:*Tandem repeats:**Satellite DNA**Minisatellite**Microsatellite*Interspersed repeats:**SINEs...
preceding the 5' ATG initiator codon of the RELN gene in an Italian population. Longer triplet repeats in the 5’ region were associated with an increase in autism susceptibility. However, another study of 125 multiple-incidence families and 68 single-incidence families found no significant difference between the length of the polymorphic repeats in affected and controls. Although, using a family based association test larger reelin alleles were found to be transmitted more frequently than expected to affected children. An additional study examining 158 subjects with German lineage likewise found no evidence of triplet repeat polymorphisms associated with autism. And the largest study consisting of 395 families found no association between autistic subjects and the CGG triplet repeat as well as the allele size when compared to age of first word.
Also, RELN is located at chromosome locus 7q22, which is associated with susceptibility with autism, and reduced levels of Reelin are found in autistic brains examined postmortem. More recent reports found conflicting results, with some finding an association between RELN and autism, and others not. Studies of transgenic
Genetically modified organism
A genetically modified organism or genetically engineered organism is an organism whose genetic material has been altered using genetic engineering techniques. These techniques, generally known as recombinant DNA technology, use DNA molecules from different sources, which are combined into one...
mice have been suggestive of an association, but not definitive.
Temporal lobe epilepsy: granule cell dispersion
Decreased reelin expression in the hippocampal tissue samples from patients with temporal lobe epilepsyTemporal lobe epilepsy
Temporal lobe epilepsy a.k.a. Psychomotor epilepsy, is a form of focal epilepsy, a chronic neurological condition characterized by recurrent seizures. Over 40 types of epilepsies are known. They fall into two main categories: partial-onset epilepsies and generalized-onset epilepsies...
was found to be directly correlated with the extent of granule cell
Granule cell
In neuroscience, granule cells refer to tiny neurons that are around 10 micrometres in diameter. Granule cells are found within the granular layer of the cerebellum , the dentate gyrus of the...
dispersion (GCD), a major feature of the disease that is noted in 45%-73% of patients. The dispersion, according to a small study, is associated with the RELN promoter hypermethylation. According to one study, prolonged seizures in a rat model of mesial temporal lobe epilepsy have led to the loss of reelin-expressing interneurons and subsequent ectopic chain migration and aberrant integration of newborn dentate granule cells. Without reelin, the chain-migrating neuroblasts failed to detach properly. Moreover, in a kainate-induced mouse epilepsy model, exogenous reelin had prevented GCD, according to one study.
Alzheimer's disease
The Reelin receptors ApoER2 and VLDLR belong to the LDL receptor gene family. All members of this family are receptors for Apolipoprotein EApolipoprotein E
Apolipoprotein E is a class of apolipoprotein found in the chylomicron and IDLs that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.-Function:...
(ApoE). Therefore, they are often synonymously referred to as 'ApoE receptors'. ApoE occurs in 3 common isoforms (E2, E3, E4) in the human population. ApoE4 is the primary genetic risk factor for late-onset Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. This strong genetic association has led to the proposal that ApoE receptors play a central role in the pathogenesis of Alzheimer's Disease. According to one study, reelin expression and glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
patterns are altered in Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. In the cortex of the patients, reelin levels were 40% higher compared with controls, but the cerebellar levels of the protein remain normal in the same patients. This finding is in agreement with an earlier study showing the presence of Reelin associated with amyloid plaques in a transgenic AD mouse model. A large genetic study of 2008 showed that RELN gene variation is associated with an increased risk of Alzheimer's disease in women. The number of reelin-producing Cajal-Retzius cells is significantly decreased in the first cortical layer of patients. Reelin has been shown to interact with amyloid precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
, and, according to one in-vitro study, is able to counteract the Aβ-induced dampening of NMDA-receptor activity. This is modulated by ApoE isoforms, which selectively alter the recycling of ApoER2 as well as AMPA and NMDA receptors.
Cancer
DNA methylationDNA methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring...
patterns are often changed in tumours, and the RELN gene could be affected: according to one study, in the pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
the expression is suppressed, along with other reelin pathway components In the same study, cutting the reelin pathway in cancer cells that still expressed reelin resulted in increased motility and invasiveness. On the contrary, in prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
the RELN expression is excessive and correlates with Gleason score
Gleason score
The Gleason Grading system is used to help evaluate the prognosis of men with prostate cancer. Together with other parameters, it is incorporated into a strategy of prostate cancer staging which predicts prognosis and helps guide therapy. A Gleason score is given to prostate cancer based upon its...
. Retinoblastoma
Retinoblastoma
Retinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...
presents another example of RELN overexpression.
Other conditions
One genome-wide association studyGenome-wide association study
In genetic epidemiology, a genome-wide association study , also known as whole genome association study , is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait...
indicates a possible role for RELN gene variation in otosclerosis
Otosclerosis
Otosclerosis is an abnormal growth of bone near the middle ear. It can result in hearing loss.-Clinical description:Otosclerosis can result in conductive and/or sensorineural hearing loss...
, an abnormal growth of bone of the middle ear
Middle ear
The middle ear is the portion of the ear internal to the eardrum, and external to the oval window of the cochlea. The mammalian middle ear contains three ossicles, which couple vibration of the eardrum into waves in the fluid and membranes of the inner ear. The hollow space of the middle ear has...
. In a statistical search for the genes that are differentially expressed in the brains of cerebral malaria-resistant versus cerebral malaria-susceptible mice, Delahaye et al. detected a significant upregulation of both RELN and DAB1
DAB1
The Disabled-1 gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway...
and speculated on possible protective effects of such over-expression.
Factors affecting reelin expression
TBR1
T-box, brain, 1 is a protein that in humans is encoded by the TBR1 gene. This gene is also known by several other names: T-Brain 1, TBR-1, TES-56, and MGC141978. TBR1 is a member of the T-box family of transcription factors that share a common DNA-binding domain...
transcription factor regulates RELN along with other T-element-containing genes. On a higher level, increased maternal care was found to correlate with reelin expression in rat pups; such correlation was reported in hippocampus and in the cortex. According to one report, prolonged exposure to corticosterone
Corticosterone
Corticosterone is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands.-Roles:In many species, including amphibians, reptiles, rodents and birds, corticosterone is a main glucocorticoid, involved in regulation of fuel, immune reactions, and stress...
significantly decreased reelin expression in murine hippocampi, a finding possibly pertinent to the hypothetical role of corticosteroids in depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
. One small postmortem study has found increased methylation of RELN gene in the neocortex of persons past their puberty compared with those that had yet to enter the period of maturation.
Psychotropic medication
As reelin is being implicated in a number of brain disorders and its expression is usually measured posthumously, assessing the possible medication effects is important.According to the epigenetic hypothesis, drugs that shift the balance in favour of demethylation have a potential to alleviate the proposed methylation-caused downregulation of RELN and GAD67. In one study, clozapine and sulpiride but not haloperidol and olanzapine were shown to increase the demethylation of both genes in mice pretreated with l-methionine. Valproic acid, a histone deacetylase inhibitor, when taken in combination with antipsychotics, is proposed to have some benefits. But there are studies conflicting the main premise of the epigenetic hypothesis, and a study by Fatemi et al. shows no increase in RELN expression by valproic acid; that indicates the need for further investigation.
Fatemi et al. conducted the study in which RELN mRNA and reelin protein levels were measured in rat prefrontal cortex following a 21-day of intraperitoneal injection
Intraperitoneal injection
Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum . IP injection is more often applied to animals than humans...
s of the following drugs:
| Reelin expression | Clozapine Clozapine Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew... |
Fluoxetine Fluoxetine Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company... |
Haloperidol Haloperidol Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines.... |
Lithium Lithium Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly... |
Olanzapine Olanzapine Olanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder... |
Valproic Acid Valproic acid Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia... |
|---|---|---|---|---|---|---|
| protein | ↓ | ↔ | ↓ | ↓ | ↑ | ↔ |
| mRNA | ↑ | ↑ | ↓ | ↑ | ↑ | ↓ |
In 2009, Fatemi et al. published the more detailed work on rats using the same medication. Here, cortical expression of several participants (VLDLR, DAB1
DAB1
The Disabled-1 gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway...
, GSK3B
GSK3B
Glycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that in humans is encoded by the GSK3B gene.- Function :Glycogen synthase kinase-3 is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase. Two isoforms,...
) of the signaling chain was measured besides reelin itself, and also the expression of GAD65 and GAD67.
Recommended reading
- The book:
- A review: