Growth cone
A growth cone is a dynamic, 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...

-supported extension of a developing axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....

 seeking its synaptic
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...

 target. Their existence was originally proposed by Spanish
Spanish people
The Spanish are citizens of the Kingdom of Spain. Within Spain, there are also a number of vigorous nationalisms and regionalisms, reflecting the country's complex history....

Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...

 Santiago Ramón y Cajal
Santiago Ramón y Cajal
Santiago Ramón y Cajal ForMemRS was a Spanish pathologist, histologist, neuroscientist, and Nobel laureate. His pioneering investigations of the microscopic structure of the brain were original: he is considered by many to be the father of modern neuroscience...

 based upon stationary images he observed under the microscope
A microscope is an instrument used to see objects that are too small for the naked eye. The science of investigating small objects using such an instrument is called microscopy...

. He first described the growth cone based on fixed cells as “a concentration of protoplasm of conical form, endowed with amoeboid movements” (Cajal, 1890). Neuronal growth cones are situated on the very tips of nerve cells on structures called axons and dendrites. The sensory, motor, integrative, and adaptive functions of growing axons and dendrites are all contained within this specialized structure.


The morphology of the growth cone can be easily described by using the hand as an analogy. The fine extensions of the growth cone are known as "filopodia
Filopodia are slender cytoplasmic projections that extend beyond the leading edge of lamellipodia in migrating cells. They contain actin filaments cross-linked into bundles by actin-binding proteins, e.g. fascin and fimbrin. Filopodia form focal adhesions with the substratum, linking it to the...

" or microspikes. The filopodia
Filopodia are slender cytoplasmic projections that extend beyond the leading edge of lamellipodia in migrating cells. They contain actin filaments cross-linked into bundles by actin-binding proteins, e.g. fascin and fimbrin. Filopodia form focal adhesions with the substratum, linking it to the...

 are like the "fingers" of the growth cone; they contain bundles of actin filaments (F-actin) that give them shape and support. Filopodia are the dominant structures in growth cones, and they appear as narrow cylindrical extensions which can extend several micrometres beyond the edge of the growth cone. The filopodia are bound by membrane which contains receptors
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...

 and cell adhesion molecules that are important for axon growth and guidance
Axon guidance
Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach the correct targets...


In between filopodia--much like the webbing of the hands--are the "lamellipodia
The lamellipodium is a cytoskeletal protein actin projection on the mobile edge of the cell. It contains a quasi-two-dimensional actin mesh; the whole structure propels the cell across a substrate...

". These are flat regions of dense actin meshwork instead of bundled F-actin as in filopodia. They often appear adjacent to the leading edge of the growth cone and are positioned between two filopodia, giving them a “veil-like” appearance. In growth cones, new filopodia usually emerge from these inter-filopodial veils.

The growth cone is described in terms of three regions: the peripheral (P) domain, the transitional (T) domain, and the central (C) domain. The peripheral domain is the thin region surrounding the outer edge of the growth cone. It is composed primarily of an actin-based cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...

, and contains the lamellipodia and filopodia which are highly dynamic. Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...

s, however, are known to transiently enter the peripheral region via a process called dynamic instability. The central domain is located in the center of the growth cone nearest to the axon. This region is composed primarily of a microtubule-based cytoskeleton, is generally thicker, and contains many organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....

s and vesicles
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...

 of various sizes. The transitional domain is the region located in the thin band between the central and peripheral domains.

There are also many cytoskeletal-associated proteins, which perform a variety of duties within the growth cone, such as anchoring actin and microtubules to each other, to the membrane, and to other cytoskeletal components. Some of these components include molecular motors that generate force within the growth cone and membrane-bound vesicles which are transported in and out of the growth cone via microtubules. Some examples of cytoskeletal-associated proteins are Fascin
Fascin is a actin cross-linking protein.It is a 54-58 kilodalton monomeric actin filament bundling protein originally isolated from sea urchin egg but also found in Drosophila and vertebrates, including humans. Fascin is spaced at 11 nanometre intervals along the filament...

 and Filamin (actin bundling), Talin
Talin protein
Talin is a high-molecular-weight cytoskeletal protein concentrated at regions of cell–substratum contact and, in lymphocytes, at cell–cell contacts. Discovered in 1983 by Keith Burridge and colleagues, talin is a ubiquitous cytosolic protein that is found in high concentrations in focal adhesions...

 (actin anchoring), myosin
Myosins comprise a family of ATP-dependent motor proteins and are best known for their role in muscle contraction and their involvement in a wide range of other eukaryotic motility processes. They are responsible for actin-based motility. The term was originally used to describe a group of similar...

 (vesicle transport), and mDia (microtubule-actin linking).

Axon branching and outgrowth

The highly dynamic nature of growth cones allows them to respond to the surrounding environment by rapidly changing direction and branching in response to various stimuli. There are three stages of axon outgrowth, which are termed: protrusion, engorgement, and consolidation. During protrusion, there is a rapid extension of filopodia and lamellar extensions along the leading edge of the growth cone. Engorgement follows when the filopodia move to the lateral edges of the growth cone, and microtubules invade further into the growth cone, bringing vesicles and organelles such as mitochondria and endoplasmic reticulum. Finally, consolidation occurs when the F-actin at the neck of the growth cone depolymerizes and the filopodia retract. The membrane then shrinks to form a cylindrical axon shaft around the bundle of microtubules. Axon branching also occurs via the same process, except that the growth cone “splits” during the engorgement phase.

Overall, axon elongation is the product of a process known as tip growth. In this process, new material is added at the growth cone while the remainder of the axonal cytoskeleton remains stationary. This occurs via two processes: cytoskeletal-based dynamics and mechanical tension. With cytoskeletal dynamics, microtubules polymerize into the growth cone and deliver vital components. Mechanical tension occurs when the membrane is stretched due to force generation by molecular motors in the growth cone and strong adhesions to the substrate along the axon. In general, rapidly growing growth cones are small and have a large degree of stretching, while slow moving or paused growth cones are very large and have a low degree of stretching.

The growth cones are continually being built up through construction of the actin microfilaments and extension of the plasma membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

 via vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...

 fusion. The actin filaments depolymerize and disassemble on the proximal end to allow free monomers to migrate to the leading edge (distal end) of the actin filament where it can polymerize and thus reattach. Actin filaments are also constantly being transported away from the leading edge by a myosin-motor driven process known as retrograde F-actin flow. The actin filaments are polymerized in the peripheral region and then transported backward to the transitional region, where the filaments are depolymerized; thus freeing the monomers to repeat the cycle. This is different from actin treadmilling since the entire protein moves. If the protein were to simply treadmill, the monomers would depolymerize from one end and polymerize onto the other while the protein itself does not move.

The growth capacity of the axons lies in the microtubules which are located just beyond the actin filaments. Microtubules can rapidly polymerize into and thus “probe” the actin-rich peripheral region of the growth cone. When this happens, the polymerizing ends of microtubules come into contact with F-actin adhesion sites, where microtubule tip-associated proteins act as "ligands". Laminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...

s of the basal membrane
Basal lamina
The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often confused with the basement membrane, and sometimes used inconsistently in the literature, see below....

 interact with the 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....

s of the growth cone to promote the forward movement of the growth cone. Additionally, axon outgrowth is also supported by the stabilization of the proximal ends of microtubules, which provide the structural support for the axon.

Axon guidance

Movement of the axons is controlled by an integration of its sensory and motor function (described above) which is established through second messengers such as calcium and cyclic nucleotides. The sensory function of axons is dependent on cues from the extracellular matrix which can be either attractive or repulsive, thus helping to guide the axon away from certain paths and attracting them to their proper target destinations. Attractive cues inhibit retrograde flow of the actin filaments and promote their assembly whereas repulsive cues have the exact opposite effect. Actin stabilizing proteins are also involved and are essential for continued protrusion of filopodia and lamellipodia in the presence of attractive cues, while actin destabilizing proteins are involved in the presence of a repulsive cue.

A similar process is involved with microtubules. In the presence of an attractive cue on one side of the growth cone, specific microtubules are targeted on that side by microtubule stabilizing proteins, resulting in growth cone turning in the direction of the positive stimulus. With repulsive cues, the opposite is true: microtubule stabilization is favored on the opposite side of the growth cone as the negative stimulus resulting in the growth cone turning away from the repellent. This process coupled with actin-associated processes result in the overall directed growth of an axon.

Growth cone receptors detect the presence of axon guidance molecules such as Netrin
Netrins are a class of proteins involved in axon guidance. They are named after the Sanskrit word "netr", which means "one who guides." Netrins are genetically conserved across nematode worms, fruitflies, frogs, and mice. Structurally, netrin resembles laminin.Netrins are chemotropic; a growing...

, Slit, Ephrin
Eph receptor
Eph receptors are components of cell signalling pathways involved in animal growth and development, forming the largest sub-family of receptor tyrosine kinases . The extracellular domain of an Eph receptor interacts with ephrin ligands, which may be tethered to neighbouring cells...

s, and Semaphorin
Semaphorins are a class of secreted and membrane proteins that act as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes. They are usually cues to deflect axons from inappropriate regions, especially...

s. It has more recently been shown that cell fate determinants such as 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:...

 or Shh
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...

 can also act as guidance cues. Quite interestingly, the same guidance cue can act as an attractant or a repellent, depending on context. A prime example of this is Netrin-1, which signals attraction through the DCC receptor and repulsion through the Unc-5 receptor. Furthermore, it has been discovered that these same molecules are involved in guiding vessel growth. Axon guidance directs the initial wiring of the nervous system and is also important in axonal regeneration following an injury.
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