Axon guidance (also called axon pathfinding) is a subfield of
neural development concerning the process by which
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s send out
axon
An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...
s to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they manage to find their way so accurately is an area of ongoing research.
Axon growth takes place from a region called the
growth cone
A growth cone is a large actin-supported extension of a developing or regenerating neurite seeking its synaptic target. It is the growth cone that drives axon growth. Their existence was originally proposed by Spanish histologist Santiago Ram ...
and reaching the axon target is accomplished with relatively few guidance molecules. Growth cone receptors respond to the guidance cues.
Mechanisms
Growing axons have a highly motile structure at the growing tip called the
growth cone
A growth cone is a large actin-supported extension of a developing or regenerating neurite seeking its synaptic target. It is the growth cone that drives axon growth. Their existence was originally proposed by Spanish histologist Santiago Ram ...
, which responds to signals in the extracellular environment that instruct the axon in which direction to grow. These signals, called guidance cues, can be fixed in place or diffusible; they can attract or repel axons. Growth cones contain
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
that recognize these guidance cues and interpret the signal into a
chemotropic response. The general theoretical framework is that when a growth cone "senses" a guidance cue, the receptors activate various signaling molecules in the growth cone that eventually affect the
cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is com ...
. If the growth cone senses a gradient of guidance cue, the intracellular signaling in the growth cone happens asymmetrically, so that cytoskeletal changes happen asymmetrically and the growth cone turns toward or away from the guidance cue.
A combination of genetic and biochemical methods (see below) has led to the discovery of several important classes of axon guidance molecules and their receptors:
*
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, fruit flies, frogs, mice, and humans. Structurall ...
s: Netrins are secreted molecules that can act to attract or repel axons by binding to their receptors,
DCC and
UNC-5
UNC-5 is a receptor for netrins including UNC-6. Netrins are a class of proteins involved in axon guidance. UNC-5 uses repulsion to direct axons while the other netrin receptor UNC-40 attracts axons to the source of netrin production.
Discove ...
.
*
Slits
The Slits were a punk and post-punk band based in London, formed there in 1976 by members of the groups the Flowers of Romance and the Castrators. The group's early line-up consisted of Ari Up (Ariane Forster) and Palmolive (a.k.a. Paloma R ...
: Secreted proteins that normally repel growth cones by engaging
Robo
Robo may refer to:
*robot, an electro-mechanical device that can perform autonomous or preprogrammed tasks
*Automation (robo-), roboticization
*Robo (musician) (born 1955), Roberto Valverde, drummer in punk bands Black Flag and The Misfits
*Robo ( ...
(Roundabout) class receptors in
Slit-Robo
Slit-Robo is the name of a cell signaling protein complex with many diverse functions including axon guidance and angiogenesis.
Slit (gene), Slit refers to a secreted protein that is most widely known as a repulsive axon guidance cue, and Roundab ...
cell signaling
In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
complexes.
*
Ephrin
Ephrins (also known as ephrin ligands or Eph family receptor interacting proteins) are a family of proteins that serve as the ligands of the Eph receptor. Eph receptors in turn compose the largest known subfamily of receptor protein-tyrosine kinas ...
s: Ephrins are cell surface molecules that activate Eph receptors on the surface of other cells. This interaction can be attractive or repulsive. In some cases, Ephrins can also act as receptors by transducing a signal into the expressing cell, while Ephs act as the ligands. Signaling into both the Ephrin- and Eph-bearing cells is called "bi-directional signaling."
*
Semaphorins
Semaphorins are a class of secreted and membrane proteins that were originally identified as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes. Semaphorins ...
: The many types of semaphorins are primarily axonal repellents, and activate complexes of cell-surface receptors called
plexins
A plexin is a protein which acts as a receptor for semaphorin family signaling proteins. It is classically known for its expression on the surface of axon growth cones and involvement in signal transduction to steer axon growth away from the sou ...
and
neuropilins.
*
Cell adhesion molecules (CAMs): Integral membrane proteins mediating adhesion between growing axons and eliciting intracellular signalling within the growth cone. CAMs are the major class of proteins mediating correct axonal navigation of axons growing on axons (fasciculation). There are two CAM subgroups: IgSF-CAMs (belonging to the immunoglobulin superfamily) and Cadherins (Ca-dependent CAMs).
In addition, many other classes of extracellular molecules are used by growth cones to navigate properly:
*Developmental morphogens, such as BMPs, Wnts,
Hedgehog
A hedgehog is a spiny mammal of the subfamily Erinaceinae, in the eulipotyphlan family Erinaceidae. There are seventeen species of hedgehog in five genera found throughout parts of Europe, Asia, and Africa, and in New Zealand by introductio ...
, and FGFs
*Extracellular matrix and adhesion molecules such as laminin, tenascins, proteoglycans, N-CAM, and L1
*Growth factors like NGF
*Neurotransmitters and modulators like GABA
Integration of information in axon guidance
Growing axons rely on a variety of guidance cues in deciding upon a growth pathway. The growth cones of extending axons process these cues in an intricate system of signal interpretation and integration, in order to ensure appropriate guidance. These cues can be functionally subdivided into:
*Adhesive cues, that provide physical interaction with the substrate necessary for axon protrusion. These cues can be expressed on glial and neuronal cells the growing axon contacts or be part of the extracellular matrix. Examples are laminin or fibronectin, in the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...
, and
cadherins or Ig-family
cell-adhesion molecule
Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
s, found on cell surfaces.
*Tropic cues, that can act as attractants or repellents and cause changes in growth cone motility by acting on the cytoskeleton through intracellular signaling. For example, Netrin plays a role in guiding axons through the midline, acting as both an attractant and a repellent, while Semaphorin3A helps axons grow from the olfactory epithelium to map different locations in the
olfactory bulb
The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex ( ...
.
*Modulatory cues, that influence the sensitivity of growth cones to certain guidance cues. For instance,
neurotrophins
Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.
They belong to a class of growth factors, secreted proteins that can signal particular cells to survive, differentiate, or grow. Growth facto ...
can make axons less sensitive to the repellent action of Semaphorin3A.
Given the abundance of these different guidance cues it was previously believed that growth cones integrate various information by simply summing the gradient of cues, in different valences, at a given point in time, to making a decision on the direction of growth. However, studies in vertebrate nervous systems of ventral midline crossing axons, has shown that modulatory cues play a crucial part in tuning axon responses to other cues, suggesting that the process of axon guidance is nonlinear. For example,
commissural
A commissure () is the location at which two objects abut or are joined. The term is used especially in the fields of anatomy and biology.
* The most common usage of the term refers to the brain's commissures, of which there are five. Such a commi ...
axons are attracted by Netrin and repelled by Slit. However, as axons approach the midline, the repellent action of Slit is suppressed by Robo-3/Rig-1 receptor. Once the axons cross the midline, activation of Robo by Slit silences Netrin-mediated attraction, and the axons are repelled by Slit.
Cellular strategies of nerve tract formation
Pioneer axons
The formation of a nerve tract follows several basic rules. In both invertebrate and vertebrate nervous systems initial nerve tracts are formed by the
pioneer axon
Pioneer axon is the classification given to axons that are the first to grow in a particular region. They originate from pioneer neurons, and have the main function of laying down the initial growing path that subsequent growing axons, dubbed follo ...
s of
pioneer neuron
A pioneer neuron is a cell that is a derivative of the preplate in the early stages of corticogenesis of the brain. Pioneer neurons settle in the marginal zone of the cortex and project to sub-cortical levels. In the rat, pioneer neurons are only ...
s. These axons follow a reproducible pathway, stop at intermediate targets, and branch axons at certain choice points, in the process of targeting their final destination. This principle is illustrated by CNS extending axons of sensory neurons in insects.
During the process of
limb development
Limb development in vertebrates is an area of active research in both developmental and evolutionary biology, with much of the latter work focused on the transition from fin to limb.
Limb formation begins in the morphogenetic limb field, as mes ...
, proximal neurons are the first to form axonal bundles while growing towards the CNS. In later stages of limb growth, axons from more distal neurons fasciculate with these pioneer axons. Deletion of pioneer neurons disrupts the extension of later axons, destined to innervate the CNS. At the same time, it is worth noting that in most cases pioneer neurons do not contain unique characteristics and their role in axon guidance can be substituted by other neurons. For instance, in
Xenopus
''Xenopus'' () (Gk., ξενος, ''xenos''=strange, πους, ''pous''=foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described within it. The two best-know ...
retinotectal connection systems, the pioneer axons of retinal ganglion cells originate from the dorsal part of the eye. However, if the dorsal half of the eye is replaced by less mature dorsal part, ventral neurons can replace the pioneer pathway of the dorsal cells, after some delay. Studies in
zebrafish
The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ca ...
retina
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
showed that inhibiting neural differentiation of early retinal progenitors prevents axons from exiting the eye. The same study demonstrated aberrant growth trajectories in secondary neurons, following the growth of pioneer neurons missing a guidance receptor. Thus, while the extent of guidance provided by pioneer axons is under debate and may vary from system to system, the pioneer pathways clearly provide the follower projections with guidance cues and enhance their ability to navigate to target.
Role of glia
The first extending axons in a pathway interact closely with immature glia cells. In the forming
corpus callosum
The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental m ...
of vertebrates, primitive glia cells first migrate to the ependymal zones of hemispheres and the dorsal septum wall to form a transient structure that the pioneer axons of the
callosal fibers use to extend. The signaling between glia and neurons in the developing nervous system is reciprocal. For instance, in the fly visual system, axons of photoreceptors require glia to exit the eye stalk whereas glia cells rely on signals from neurons to migrate back along axons.
Guideposts
The growing axons also rely on transient neuronal structures such as
guidepost cells, during pathfinding. In the mouse
visual system
The visual system comprises the sensory organ (the eye) and parts of the central nervous system (the retina containing photoreceptor cells, the optic nerve, the optic tract and the visual cortex) which gives organisms the sense of sight (th ...
, proper
optic chiasm
In neuroanatomy, the optic chiasm, or optic chiasma (; , ), is the part of the brain where the optic nerves cross. It is located at the bottom of the brain immediately inferior to the hypothalamus. The optic chiasm is found in all vertebrat ...
formation depends on a V-shaped structure of transient neurons that intersect with specialized radial glia at the midline of the chiasm. The chiasm axons grow along and around this structure but do not invade it. Another example is the subplate in the developing
cerebral cortex
The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consistin ...
that consists of transient neuronal layer under the
subventricular zone
The subventricular zone (SVZ) is a region situated on the outside wall of each lateral ventricle of the vertebrate brain. It is present in both the embryonic and adult brain. In embryonic life, the SVZ refers to a secondary proliferative zone ...
and serves as a guidepost for axons entering permanent cortical layers. The subplate is similar to the chiasmatic neurons in that these cell groups disappear (or transit into other cell types) as the brain matures. These findings indicate that transitory cell populations can serve an important guidance role even though they have no function in the mature nervous system.
Studying axon guidance
The earliest descriptions of the axonal growth cone were made by the Spanish neurobiologist
Santiago Ramón y Cajal
Santiago Ramón y Cajal (; 1 May 1852 – 17 October 1934) was a Spanish neuroscientist, pathologist, and histologist specializing in neuroanatomy and the central nervous system. He and Camillo Golgi received the Nobel Prize in Physiology or Me ...
in the late 19th century. However, understanding the molecular and cellular biology of axon guidance would not begin until decades later. In the last thirty years or so, scientists have used various methods to work out how axons find their way. Much of the early work in axon guidance was done in the
grasshopper, where individual motor neurons were identified and their pathways characterized. In genetic
model organisms
A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the working ...
like
mice,
zebrafish
The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ca ...
,
nematodes
The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-parasitic nematodes also known as eelworms. They are a diverse animal phylum inhabiting a broa ...
, and
fruit flies
Fruit fly may refer to:
Organisms
* Drosophilidae, a family of small flies, including:
** ''Drosophila'', the genus of small fruit flies and vinegar flies
** ''Drosophila melanogaster'' or common fruit fly
** '' Drosophila suzukii'' or Asian frui ...
, scientists can generate
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
s and see whether and how they cause axons to make errors in navigation.
In vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...
experiments can be useful for direct manipulation of growing axons. A popular method is to grow neurons in culture and expose growth cones to purified guidance cues to see whether these cause the growing axons to turn. These types of experiments have often been done using traditional embryological non-genetic model organisms, such as the
chicken
The chicken (''Gallus gallus domesticus'') is a domesticated junglefowl species, with attributes of wild species such as the grey and the Ceylon junglefowl that are originally from Southeastern Asia. Rooster or cock is a term for an adu ...
and
African clawed frog
The African clawed frog (''Xenopus laevis'', also known as the xenopus, African clawed toad, African claw-toed frog or the ''platanna'') is a species of African aquatic frog of the family Pipidae. Its name is derived from the three short claws o ...
. Embryos of these species are easy to obtain and, unlike mammals, develop externally and are easily accessible to experimental manipulation.
Axon guidance model systems
Several types of axon pathways have been extensively studied in model systems to further understand the mechanisms of axon guidance. Perhaps the two most prominent of these are commissures and topographic maps. Commissures are sites where axons cross the midline from one side of the nervous system to the other. Topographic maps are systems in which groups of neurons in one tissue project their axons to another tissue in an organized arrangement such that spatial relationships are maintained; i.e. adjacent neurons will innervate adjacent regions of the target tissue.
Commissure formation: attraction and repulsion
As described above, axonal guidance cues are often categorized as "attractive" or "repulsive." This is a simplification, as different axons will respond to a given cue differently. Furthermore, the same axonal growth cone can alter its responses to a given cue based on timing, previous experience with the same or other cues, and the context in which the cue is found. These issues are exemplified during the development of commissures. The bilateral symmetry of the nervous system means that axons will encounter the same cues on either side of the midline. Before crossing (ipsilaterally), the growth cone must navigate toward and be attracted to the midline. However, after crossing (contralaterally), the same growth cone must become repelled or lose attraction to the midline and reinterpret the environment to locate the correct target tissue.
Two experimental systems have had particularly strong impacts on understanding how midline axon guidance is regulated:
=The ventral nerve cord of ''Drosophila''
=
![Axonal pathfinding and fasciculation behaviour in the embryonic ventral nerve cord of Drosophila](https://upload.wikimedia.org/wikipedia/commons/f/f6/Axonal_pathfinding_and_fasciculation_behaviour_in_the_embryonic_ventral_nerve_cord_of_Drosophila.jpg)
The use of powerful genetic tools in ''Drosophila'' led to the identification of a key class of axon guidance cues, the Slits, and their receptors, the Robos (short for Roundabout). The
ventral nerve cord
The ventral nerve cord is a major structure of the invertebrate central nervous system. It is the functional equivalent of the vertebrate spinal cord. The ventral nerve cord coordinates neural signaling from the brain to the body and vice versa, i ...
looks like a ladder, with three longitudinal axon bundles (fascicles) connected by the commissures, the "rungs" of the ladder. There are two commissures, anterior and posterior, within each segment of the embryo.
The currently accepted model is that Slit, produced by midline cells, repels axons from the midline via Robo receptors. Ipsilaterally projecting (non-crossing) axons always have Robo receptors on their surface, while commissural axons have very little or no Robo on their surface, allowing them to be attracted to the midline by Netrins and, probably, other as-yet unidentified cues. After crossing, however, Robo receptors are strongly upregulated on the axon, which allows Robo-mediated repulsion to overcome attraction to the midline. This dynamic regulation of Robo is at least in part accomplished by a molecule called Comm (short for Commissureless), which prevents Robo from reaching the cell surface and targeting it for destruction.
=The spinal cord of mice and chickens
=
In the spinal cord of vertebrates, commissural neurons from the dorsal regions project downward toward the ventral floor plate. Ipsilateral axons turn before reaching the floor plate to grow longitudinally, while commissural axons cross the midline and make their longitudinal turn on the contralateral side. Strikingly, Netrins, Slits, and Robos all play similar functional roles in this system as well. One outstanding mystery was the apparent lack of any ''comm'' gene in vertebrates. It now seems that at least some of Comm's functions are performed by a modified form of Robo called Robo3 (or Rig1).
The spinal cord system was the first to demonstrate explicitly the altered responsiveness of growth cones to cues after exposure to the midline. Explanted neurons grown in culture would respond to exogenously supplied Slit according to whether or not they had contacted floor plate tissue.
Topographic maps: gradients for guidance
As described above, topographic maps occur when spatial relationships are maintained between neuronal populations and their target fields in another tissue. This is a major feature of nervous system organization, particular in sensory systems. The neurobiologist
Roger Sperry
Roger Wolcott Sperry (August 20, 1913 – April 17, 1994) was an American neuropsychologist, neurobiologist, cognitive neuroscientist, and Nobel laureate who, together with David Hunter Hubel and Torsten Nils Wiesel, won the 1981 Nobel Prize i ...
proposed a prescient model for topographic mapping mediated by what he called molecular "tags." The relative amounts of these tags would vary in gradients across both tissues. We now think of these tags as ligands (cues) and their axonal receptors. Perhaps the best understood class of tags are the Ephrin ligands and their receptors, the Ephs.
In the simplest type of mapping model, we could imagine a gradient of Eph receptor expression level in a field of neurons, such as the retina, with the anterior cells expressing very low levels and cells in the posterior expressing the highest levels of the receptor. Meanwhile, in the target of the retinal cells (the
optic tectum
In neuroanatomy, the superior colliculus () is a structure lying on the roof of the mammalian midbrain. In non-mammalian vertebrates, the homologous structure is known as the optic tectum, or optic lobe. The adjective form '' tectal'' is commonl ...
), Ephrin ligands are organized in a similar gradient: high posterior to low anterior. Retinal axons enter the anterior tectum and proceed posteriorly. Because, in general, Eph-bearing axons are repelled by Ephrins, axons will become more and more reluctant to proceed the further they advance toward the posterior tectum. However, the degree to which they are repelled is set by their own particular level of Eph expression, which is set by the position of the neuronal cell body in the retina. Thus, axons from the anterior retina, expressing the lowest level of Ephs, can project to the posterior tectum, even though this is where Ephrins are highly expressed. Posterior retinal cells express high Eph level, and their axons will stop more anteriorly in the tectum.
=The retinotectal projection of chickens, frogs and fish
=
The large size and accessibility of the chicken embryo has made it a favorite model organism for embryologists. Researchers used the chick to biochemically purify components from the tectum that showed specific activity against retinal axons in culture. This led to the identification of Ephs and Ephrins as Sperry's hypothesized "tags."
The retinotectal projection has also been studied in ''Xenopus'' and zebrafish. Zebrafish is a potentially powerful system because genetic screens like those performed in invertebrates can be done relatively simply and cheaply. In 1996, large scale screens were conducted in zebrafish, including screens for retinal axon guidance and mapping. Many of the mutants have yet to be characterized.
Cell biology
Genetics
Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar wor ...
and
biochemistry
Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
have identified a large set of molecules that affect axon guidance. How all of these pieces fit together is less understood. Most axon guidance receptors activate signal transduction cascades that ultimately lead to reorganization of the
cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is com ...
and adhesive properties of the growth cone, which together underlie the motility of all cells. This has been well documented in mammalian cortical neurons. However, this raises the question of how the same cues can result in a spectrum of response from different growth cones. It may be that different receptors activate attraction or repulsion in response to a single cue. Another possibility is the receptor complexes act as "coincidence detectors" to modify responses to one cue in the presence of another. Similar signaling "cross-talk" could occur intracellularly, downstream of receptors on the cell surface.
In fact, commissural axon growth responses have been shown to be attracted, repressed, or silenced in the presence of
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, fruit flies, frogs, mice, and humans. Structurall ...
activated DCC receptor. This variable activity is dependent on Robo or UNC-5 receptor expression at growth cones. Such that Slit activated Robo receptor, causes a silencing of Netrin’s attractive potential through the DCC receptor. While growth cones expressing UNC-5 receptor, respond in a repulsive manner to Netrin-DCC activation. These events occur as consequence of cytoplasmic interactions between the Netrin activated
DCC receptor and Robo or UNC-5 receptor, which ultimately alters DCC’s cytoplasmic signaling. Thus, the picture that emerges is that growth cone advancement is highly complex and subject to plasticity from guidance cues, receptor expression, receptor interactions, and the subsequent signaling mechanisms that influence cytoskeleton remodeling.
Growth cone translation in guided axons
The ability for axons to navigate and adjust responses to various extracellular cues, at long distances from the cell body, has prompted investigators to look at the intrinsic properties of growth cones. Recent studies reveal that guidance cues can influence spatiotemporal changes in axons by modulating the local translation and degradation of proteins in growth cones. Furthermore, this activity seems to occur independent of distal nuclear gene expression. In fact, in
retinal ganglion cells (RGCs) with soma severed axons, growth cones continue to track and innervate the tectum of Xenopus embryos.
To accommodate this activity, growth cones are believed to pool
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
s that code for receptors and intracellular signaling proteins involved in cytoskeleton remodeling. In Xenopus retinotectal projection systems, the expression of these proteins has been shown to be influenced by guidance cues and the subsequent activation of local translation machinery. The attractive cue Netrin-1, stimulates mRNA transport and influence synthesis of
β-Actin
Beta-actin (human gene and protein abbreviation ''ACTB''/ACTB) is one of six different actin isoforms which have been identified in humans. This is one of the two nonmuscle cytoskeletal actins. Actins are highly conserved proteins that are invol ...
in
filopodia
Filopodia (singular filopodium) are slender cytoplasmic projections that extend beyond the leading edge of lamellipodia in migrating cells. Within the lamellipodium, actin ribs are known as ''microspikes'', and when they extend beyond the lame ...
of growth cones, to restructure and steer RGC growth cones in the direction of Netrin secretion. While the repulsive cue, Slit, is suggested to stimulate the translation of Cofilin (an actin depolymerizing factor) in growth cones, leading to axon repulsion. In addition, severed commissural axons in chicks, display the capability of translating and expressing Eph-A2 receptor during midline crossing. As a result, studies suggest that local protein expression is a convenient mechanism to explain the rapid, dynamic, and autonomous nature of growth cone advancement in response to guidance molecules.
The axon growth hypothesis and the consensus connectome dynamics
Contemporary diffusion-weighted
MRI
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
techniques may also uncover the macroscopical process of axonal development. The
connectome
A connectome () is a comprehensive map of neural connections in the brain, and may be thought of as its "wiring diagram". An organism's nervous system is made up of neurons which communicate through synapses. A connectome is constructed by tr ...
, or the braingraph, can be constructed from
diffusion MRI
Diffusion-weighted magnetic resonance imaging (DWI or DW-MRI) is the use of specific MRI sequences as well as software that generates images from the resulting data that uses the diffusion of water molecules to generate contrast in MR images. It ...
data: the vertices of the graph correspond to anatomically labelled brain areas, and two such vertices, say ''u'' and ''v'', are connected by an edge if the
tractography
In neuroscience, tractography is a 3D modeling technique used to visually represent nerve tracts using data collected by diffusion MRI. It uses special techniques of magnetic resonance imaging (MRI) and computer-based diffusion MRI. The results a ...
phase of the data processing finds an axonal fiber that connects the two areas, corresponding to ''u'' and ''v''. Numerous braingraphs, computed from the
Human Connectome Project
The Human Connectome Project (HCP) is a five-year project sponsored by sixteen components of the National Institutes of Health, split between two consortia of research institutions. The project was launched in July 2009 as the first of three Grand ...
can be downloaded from the http://braingraph.org site. The Consensus Connectome Dynamics (CCD) is a remarkable phenomenon that was discovered by continuously decreasing the minimum confidence-parameter at the graphical interface of the
Budapest Reference Connectome
The Budapest Reference Connectome server computes the frequently appearing anatomical brain connections of 418 healthy subjects.
It has been prepared from diffusion MRI datasets of the Human Connectome Project into a reference connectome (or b ...
Server.
[
][
] The Budapest Reference Connectome Server depicts the cerebral connections of n=418 subjects with a frequency-parameter k: For any k=1,2,...,n one can view the graph of the edges that are present in at least k connectomes. If parameter k is decreased one-by-one from k=n through k=1 then more and more edges appear in the graph, since the inclusion condition is relaxed. The surprising observation is that the appearance of the edges is far from random: it resembles a growing, complex structure, like a tree or a shrub (visualized on .
It is hypothesized in
that the growing structure copies the axonal development of the human brain: the earliest developing connections (axonal fibers) are common in most of the subjects, and the subsequently developing connections have larger and larger variance, because their variances are accumulated in the process of axonal development.
Genetic association
Axon guidance is genetically associated with other characteristics or features. For example,
enrichment analyses of different signaling pathways led to the discovery of a genetic association with intracranial volume.
See also
*
Pioneer axon
Pioneer axon is the classification given to axons that are the first to grow in a particular region. They originate from pioneer neurons, and have the main function of laying down the initial growing path that subsequent growing axons, dubbed follo ...
*
RTN4R mediates inhibition of axonal growth
References
{{reflist
External links
* A seminar for general audience
"Wiring up the brain: How axons navigate"
Developmental neuroscience