Morphogen
Encyclopedia
A morphogen is a substance governing the pattern of tissue development, and the positions of the various specialized cell types within a tissue. It spreads from a localized source and forms a concentration gradient across a developing tissue.
In developmental biology a morphogen is rigorously used to mean a signaling molecule that acts directly on cells (not through serial induction) to produce specific cellular responses dependent on morphogen concentration.
Well-known morphogens include: Decapentaplegic
/ Transforming growth factor beta, Hedgehog / Sonic Hedgehog
, Wingless / Wnt
, Epidermal growth factor
, Fibroblast growth factor
, and Retinoic acid
.
Morphogens are defined conceptually, not chemically, so simple compounds such as retinoic acid
(the active metabolite of retinol
or vitamin A
) may also act as morphogens.
of different target genes
at distinct concentration thresholds. Thus, cells far from the source of the morphogen will receive low levels of morphogen and express only low-threshold target genes. In contrast, cells close to the source of morphogen will receive high levels of morphogen and will express both low- and high-threshold target genes. Distinct cell types emerge as a consequence of the different combination of target gene expression. In this way, the field of cells is subdivided into different types according to their position relative to the source of the morphogen. This is a general mechanism by which cell type diversity can be generated in animal development.
Some of the earliest and best-studied morphogens are transcription factor
s that diffuse within early Drosophila melanogaster
(fruit fly) embryos. However, most morphogens are secreted proteins that signal between cells.
has an unusual developmental system, in which the first thirteen cell divisions of the embryo occur within a syncytium
prior to cellularization. Essentially the embryo remains a single cell with over 8000 nuclei evenly spaced near the membrane until the fourteenth cell division, when independent membranes furrow between the nuclei, separating them into independent cells. As a result, in fly embryos transcription factor
s such as Bicoid or Hunchback
can act as morphogens because they can freely diffuse between nuclei to produce smooth gradients of concentration without relying on specialized intercellular signalling mechanisms. Although there is some evidence that homeobox
transcription factor
s similar to these can pass directly through cell membranes, this mechanism is not believed to contribute greatly to morphogenesis in cellularized systems.
In most developmental systems, such as human embryos or later Drosophila development, syncytia occur only rarely (such as in skeletal muscle), and morphogens are generally secreted signalling proteins. These proteins bind to the extracellular domains of transmembrane receptor
proteins, which use an elaborate process of signal transduction
to communicate the level of morphogen to the nucleus. The nuclear targets of signal transduction pathways are usually transcription factors, whose activity is regulated in a manner that reflects the level of morphogen received at the cell surface. Thus, secreted morphogens act to generate gradients of transcription factor activity just like those that are generated in the syncitial Drosophila embryo.
Discrete target genes respond to different thresholds of morphogen activity. The expression of target genes is controlled by segments of DNA called 'enhancers
' to which transcription factor
s bind directly. Once bound, the transcription factor then stimulates or inhibits the transcription of the gene and thus controls the level of expression of the gene product (usually a protein). 'Low-threshold' target genes require only low levels of morphogen activity to be regulated and feature enhancers that contain many high-affinity binding sites for the transcription factor. 'High-threshold' target genes have relatively fewer binding sites or low-affinity binding sites that require much greater levels of transcription factor activity to be regulated.
Thus, the general mechanism by which morphogens subdivide tissues into patterns of distinct cell types is well understood. However, morphogens often have additional activities such as controlling the growth of the tissue or orienting the polarity of cells within it (for example, the hairs on your forearm point in one direction). These activities of morphogens are much less understood and are the subject of current research efforts in the field of developmental biology.
, in the early 20th century. However, it was Lewis Wolpert
who refined the morphogen concept in the 1960s with his famous French flag model
which described how morphogen could subdivide a tissue into domains of different target gene expression (corresponding to the colours of the French flag). This model was championed by the leading Drosophila biologist, Peter Lawrence
. Christiane Nusslein-Volhard
identified the first morphogen, Bicoid, one of the transcription factors present in a gradient in the Drosophila syncitial embryo. Two labs, that of Gary Struhl and that of Stephen Cohen, then demonstrated that a secreted signalling protein, Decapentaplegic (the Drosophila homologue of Transforming Growth Factor Beta), acted as a morphogen during later stages of Drosophila development.
Subsequent studies of the development of many different animals has confirmed the widespread importance of morphogens in governing animal development.
In developmental biology a morphogen is rigorously used to mean a signaling molecule that acts directly on cells (not through serial induction) to produce specific cellular responses dependent on morphogen concentration.
Well-known morphogens include: Decapentaplegic
Decapentaplegic
Decapentaplegic is a key morphogen involved in the development of the fruit fly Drosophila melanogaster. It is known to be necessary for the correct patterning of the fifteen imaginal discs, which are tissues that will become limbs and other organs and structures in the adult fly. It has also been...
/ Transforming growth factor beta, Hedgehog / Sonic Hedgehog
Sonic hedgehog
Sonic hedgehog homolog is one of three proteins in the mammalian signaling pathway family called hedgehog, the others being desert hedgehog and Indian hedgehog . SHH is the best studied ligand of the hedgehog signaling pathway. It plays a key role in regulating vertebrate organogenesis, such as...
, Wingless / Wnt
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
, 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...
, Fibroblast growth factor
Fibroblast growth factor
Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
, and Retinoic acid
Retinoic acid
Retinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans...
.
Morphogens are defined conceptually, not chemically, so simple compounds such as retinoic acid
Retinoic acid
Retinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans...
(the active metabolite of retinol
Retinol
Retinol is one of the animal forms of vitamin A. It is a diterpenoid and an alcohol. It is convertible to other forms of vitamin A, and the retinyl ester derivative of the alcohol serves as the storage form of the vitamin in animals....
or vitamin A
Vitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...
) may also act as morphogens.
Introduction
During early development, morphogen gradients generate different cell types in distinct spatial order. The morphogen provides spatial information by forming a concentration gradient that subdivides a field of cells by inducing or maintaining the expressionGene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of different target genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
at distinct concentration thresholds. Thus, cells far from the source of the morphogen will receive low levels of morphogen and express only low-threshold target genes. In contrast, cells close to the source of morphogen will receive high levels of morphogen and will express both low- and high-threshold target genes. Distinct cell types emerge as a consequence of the different combination of target gene expression. In this way, the field of cells is subdivided into different types according to their position relative to the source of the morphogen. This is a general mechanism by which cell type diversity can be generated in animal development.
Some of the earliest and best-studied morphogens are transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s that diffuse within early Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
(fruit fly) embryos. However, most morphogens are secreted proteins that signal between cells.
Fruit fly
Drosophila melanogasterDrosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
has an unusual developmental system, in which the first thirteen cell divisions of the embryo occur within a syncytium
Syncytium
In biology, a syncytium is a large cell-like structure; filled with cytoplasm and containing many nuclei. Most cells in eukaryotic organisms have a single nucleus; syncytia are specialized forms used by various organisms.The term may also refer to cells that are connected by specialized membrane...
prior to cellularization. Essentially the embryo remains a single cell with over 8000 nuclei evenly spaced near the membrane until the fourteenth cell division, when independent membranes furrow between the nuclei, separating them into independent cells. As a result, in fly embryos transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s such as Bicoid or Hunchback
Hunchback
Hunchback may refer to one of the following.*A derogatory term for a person who has severe kyphosis*The Hunchback of Notre Dame*Hunchback , an arcade and computer game from the 1980s*The Hunchback, a 1914 film featuring Lillian Gish...
can act as morphogens because they can freely diffuse between nuclei to produce smooth gradients of concentration without relying on specialized intercellular signalling mechanisms. Although there is some evidence that homeobox
Homeobox
A homeobox is a DNA sequence found within genes that are involved in the regulation of patterns of anatomical development in animals, fungi and plants.- Discovery :...
transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s similar to these can pass directly through cell membranes, this mechanism is not believed to contribute greatly to morphogenesis in cellularized systems.
In most developmental systems, such as human embryos or later Drosophila development, syncytia occur only rarely (such as in skeletal muscle), and morphogens are generally secreted signalling proteins. These proteins bind to the extracellular domains of transmembrane receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
proteins, which use an elaborate process of signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
to communicate the level of morphogen to the nucleus. The nuclear targets of signal transduction pathways are usually transcription factors, whose activity is regulated in a manner that reflects the level of morphogen received at the cell surface. Thus, secreted morphogens act to generate gradients of transcription factor activity just like those that are generated in the syncitial Drosophila embryo.
Discrete target genes respond to different thresholds of morphogen activity. The expression of target genes is controlled by segments of DNA called 'enhancers
Enhancer (genetics)
In genetics, an enhancer is a short region of DNA that can be bound with proteins to enhance transcription levels of genes in a gene cluster...
' to which transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s bind directly. Once bound, the transcription factor then stimulates or inhibits the transcription of the gene and thus controls the level of expression of the gene product (usually a protein). 'Low-threshold' target genes require only low levels of morphogen activity to be regulated and feature enhancers that contain many high-affinity binding sites for the transcription factor. 'High-threshold' target genes have relatively fewer binding sites or low-affinity binding sites that require much greater levels of transcription factor activity to be regulated.
Thus, the general mechanism by which morphogens subdivide tissues into patterns of distinct cell types is well understood. However, morphogens often have additional activities such as controlling the growth of the tissue or orienting the polarity of cells within it (for example, the hairs on your forearm point in one direction). These activities of morphogens are much less understood and are the subject of current research efforts in the field of developmental biology.
Discovery
The morphogen idea has a long history in developmental biology, dating back to the work of the pioneering Drosophila geneticist, Thomas Hunt MorganThomas Hunt Morgan
Thomas Hunt Morgan was an American evolutionary biologist, geneticist and embryologist and science author who won the Nobel Prize in Physiology or Medicine in 1933 for discoveries relating the role the chromosome plays in heredity.Morgan received his PhD from Johns Hopkins University in zoology...
, in the early 20th century. However, it was Lewis Wolpert
Lewis Wolpert
Lewis Wolpert CBE FRS FRSL is a developmental biologist, author, and broadcaster.-Career:Wolpert was educated at the University of Witwatersrand , at Imperial College London, and at King's College London...
who refined the morphogen concept in the 1960s with his famous French flag model
French flag model
The French Flag Model is a conceptual definition of a morphogen, described by Lewis Wolpert in the 1960s. A morphogen is rigorously defined as a signaling molecule that acts directly on cells to produce specific cellular responses dependent on morphogen concentration...
which described how morphogen could subdivide a tissue into domains of different target gene expression (corresponding to the colours of the French flag). This model was championed by the leading Drosophila biologist, Peter Lawrence
Peter Lawrence
Peter Anthony Lawrence FRS is a British developmental biologist at the Laboratory of Molecular Biology and the Zoology Department of the University of Cambridge...
. Christiane Nusslein-Volhard
Christiane Nüsslein-Volhard
Christiane Nüsslein-Volhard is a German biologist who won the Albert Lasker Award for Basic Medical Research in 1991 and the Nobel Prize in Physiology or Medicine in 1995, together with Eric Wieschaus and Edward B...
identified the first morphogen, Bicoid, one of the transcription factors present in a gradient in the Drosophila syncitial embryo. Two labs, that of Gary Struhl and that of Stephen Cohen, then demonstrated that a secreted signalling protein, Decapentaplegic (the Drosophila homologue of Transforming Growth Factor Beta), acted as a morphogen during later stages of Drosophila development.
Subsequent studies of the development of many different animals has confirmed the widespread importance of morphogens in governing animal development.