Furthermore, the distribution of fluorescent SDF1-fusion proteins expressed from genomic BAC clones closely resembled that observed by in situ hybridizations Bhattacharyya et al. It is possible that widespread diffusion is prevented by receptor-mediated clearance Boldajipour et al.
Taken together, available evidence supports the possibility of local SDF1 accumulations in the extracellular matrix of expressing cells.
Similar cell surface enrichments might also apply for Netrin-expressing cells. Secreted Netrin proteins are generally believed to attract commissural axons over long distances towards and across the midline. In the developing spinal cord, Netrin1 is expressed at highest levels in the floor plate, and hypomorphic gene-trap mice first revealed that it is required there to cross the midline Serafini et al. Removing Netrin1 completely, in null mutant mice, resulted in an even stronger phenotype, with commissural axons rarely crossing the midline at all Bin et al.
Interestingly, conditional knockouts lacking Netrin1 selectively in floor plate cells of the hindbrain showed surprisingly little crossing defects.
In contrast, deletions in neuronal progenitors of the ventricular zone prevented midline crossing, and the phenotypes were indistinguishable from null mutants. Netrin1 was detected on neuronal processes extending to the pial surface suggesting that commissural axons detect the protein there locally Dominici et al.
Latest experiments in the spinal cord similarly found evidence for a haptotactic function of Netrins but chemoattraction from the floor plate also played a role Moreno-Bravo et al.
In fact, evidence for short-range function of Netrins was also obtained in vitro and in invertebrates. Netrin-coated beads triggered traction forces and reoriented spinal commissural axons by adhesive interactions in vitro Moore et al. In addition, experiments in Drosophila showed that a membrane-tethered form of endogenous NetrinB rescued commissure formation indicating that Netrin secretion was not required Brankatschk and Dickson, Future experiments should, therefore, address the exiting question if Netrins function as substrate-derived attractants.
Direct contact-dependent adhesion to an attractive cue was recently demonstrated in C. Substrate adhesion therefore correlated well with structural changes in the underlying cytoskeleton. Such substrate-mediated cytoskeleton remodeling has been observed in various neuronal motility systems Suter and Forscher, ; Myers et al. Reorganization is usually mediated by transmembrane receptors and specialized cytoplasmic adaptor proteins thought to function as molecular clutches Lin and Forscher, ; Bard et al.
Dynamic linkage of guidance receptors to filopodial actin flow is, therefore, a possible scenario for the conversion of attractive cues into forward movements or growth cone turning. Substrate-derived attractants also play an important role during Drosophila development.
There is accumulating evidence that Sidestep Side marks permissive substrates for outgrowing motor axons Figure 1C.
Side is a transmembrane protein of the immunoglobulin family and attracts motor axons Sink et al. Motor axons pioneering the intersegmental nerve ISN leave the ventral nerve cord by growing along an array of Side-expressing cells Siebert et al. Once in the periphery, they fasciculate with Side-positive, peripheral sensory axons that grow into the CNS.
Although Side is difficult to detect in a subset of sensory axons, based on the location of the sensory clusters in the lateral body wall, major motor nerves could in principle reach their appropriate target regions by simply growing along sensory tracks followed by defasciculation into the muscle fields.
Motor axons are firmly attached to sensory axons in wild-type embryos but show detachments in side mutants Siebert et al. Beaten path Ia Beat , also a member of the immunoglobulin family, is expressed in motor neurons and functions to detect Side Fambrough and Goodman, ; Siebert et al.
First, loss of beat leads to highly similar axon guidance errors and muscle innervation phenotypes as observed in side mutants Fambrough and Goodman, ; Sink et al. A phenotype that is not increased in double mutants Siebert et al. Second, Beat and Side interact with each other in S2 cell aggregations assays and in immunoprecipitation experiments Siebert et al. Third, while Side is no longer detectable on peripheral nerves at the end of embryogenesis using Side-specific antibodies, it is constitutively expressed in beat mutants Siebert et al.
In fact, homozygous beat mutant embryos can be visually distinguished from heterozygous embryos based on Side expression, indicating that there is some sort of cross-regulation.
And fourth, Side loses its ability to attract motor axons in beat mutants Siebert et al. These results indicate that Beat on motor axons recognizes Side in substrates during the establishment of neuromuscular circuits. Drosophila peripheral nerves express several axon guidance receptors of the immunoglobulin superfamily, but in direct comparisons, Side seems to be most potent in attracting motor axons Kinold et al.
In fact, overexpression of Side, but not the homophilic adhesion proteins Fasciclin II or Neuroglian, in developing muscles irreversibly attracted dorsally-directed ISN motor axons to ventral and lateral muscle precursors Kinold et al. In addition, the expression patterns of some proteins in the Side family are consistent with a possible role as substrate-based cues Li et al. Thus, proteins of the Beat and Side family might mediate contact attraction of various pathways, highlighting the importance of the spatiotemporal expression pattern and the subcellular localization of the proteins during axon guidance by attraction.
Labeling cell surfaces along migratory routes with potent attractants might be a powerful means to steer cells and axons, irrespective of the nature of other factors nearby. Differential attraction, that is, preferred attraction to designated substrates over their surroundings, might actually be sufficient to guide cells and axons. However, I emphasize that due to space constraints other aspects of axon guidance and cell migration, such as repellents Kolodkin and Tessier-Lavigne, ; Seiradake et al.
Largely unresolved remain also the signaling mechanisms downstream of adhesion receptors and the integration of attractive and repulsive cues in the growth cone. A highly interesting point is the consequence of axon guidance errors for adult locomotion and behavior.
While several axon guidance diseases have been identified in humans Engle, , there are still only a few examples of inherited mutations affecting the wiring of the musculoskeletal system. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Affolter, M. Tracheal branching morphogenesis in Drosophila : new insights into cell behaviour and organ architecture. Development , — Amack, J. Knowing the boundaries: extending the differential adhesion hypothesis in embryonic cell sorting.
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The chemokine stromal cell-derived factor-1 regulates GABAergic inputs to neural progenitors in the postnatal dentate gyrus. Bin, J.
Complete loss of netrin-1 results in embryonic lethality and severe axon guidance defects without increased neural cell death. Cell Rep. Boldajipour, B. Control of chemokine-guided cell migration by ligand sequestration.
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A chemokine, SDF-1, reduces the effectiveness of multiple axonal repellents and is required for normal axon pathfinding. Chen, C. Cell 48, — David, N. U S A 99, — Target recognition and synaptogenesis by motor axons: responses to the sidestep protein. Dickson, B. Molecular mechanisms of axon guidance. Doitsidou, M. Guidance of primordial germ cell migration by the chemokine SDF Dominici, C. Floor-plate-derived netrin-1 is dispensable for commissural axon guidance. Du, L. Unique patterns of organization and migration of FGF-expressing cells during Drosophila morphogenesis.
Engle, E. Human genetic disorders of axon guidance. Cold Spring Harb. Fambrough, D. The Drosophila beaten path gene encodes a novel secreted protein that regulates defasciculation at motor axon choice points. Cell 87, — Friedl, P. Collective cell migration in morphogenesis, regeneration and cancer. Cell Biol. Ghysen, A. Development of the zebrafish lateral line. Curr Opin Neurobiol 14, 67— Gilmour, D. Interestingly, the timing of sensitivity to class-3 semaphorins [semaphorin 3B Sema3B and Sema3F] also seems to be regulated at the post-translational level Nawabi et al.
For instance, plexin A1, one component of the receptor for Sema3B, together with neuropilin 2 Npn-2; Nrp2 — Mouse Genome Informatics , is degraded by calpain in pre-crossing axons. When axons approach the floor plate, calpain is inactivated by NrCAM. Additional short-range axon guidance cues for dI1 navigation at the midline have been identified that affect midline crossing or turning into the longitudinal axis, or both.
For example, midline crossing is normal but turning is affected after perturbation of SynCAMs also known as nectin-like molecules; Niederkofler et al. Both floor-plate crossing and rostral turning of dI1 axons are affected after silencing Sema6B and plexin A2 in axons or plexin A2 in the floor plate Andermatt et al.
Following midline crossing, axonal navigation along the rostro-caudal axis is directed by morphogen gradients Fig. Wnts have been shown to attract post-crossing commissural axons rostrally by forming a rostral high -caudal low gradient at the floor plate Lyuksyutova et al.
At the same time, post-crossing axons are repelled by Shh, which forms a rostral low -caudal high gradient along the floor plate Bourikas et al. In contrast to the attractive effect of Shh on pre-crossing axons, which is mediated by non-canonical Shh signalling mediated by Src family kinases Yam et al.
Interestingly, Shh itself induces the change in receptor expression by binding to glypican 1 on pre-crossing axons, resulting in transcriptional regulation and expression of Hhip Wilson and Stoeckli, The functions of Shh and Wnt signalling during the rostral turning of post-crossing axons are not independent of each other Domanitskaya et al.
The graded expression of Shh has been shown to affect Wnt signalling via secreted frizzled-related proteins Sfrps , which are endogenous Wnt antagonists that soak up Wnts and prevent them from interacting with frizzled 3 Fzd3 , the Wnt receptor expressed by commissural axons.
Thus, high levels of Shh trigger high levels of Sfrps in the caudal spinal cord, thereby reducing attraction by Wnt, whereas the absence of Sfrp in the more rostral spinal cord allows for high Wnt attraction.
Recently, another link between Shh and Wnt signalling has been demonstrated Onishi and Zou, Shh was shown to regulate Fzd3 surface expression via Shisa2, which prevents Fzd3 modification and transport from the Golgi to the plasma membrane Onishi and Zou, Shh signalling keeps Shisa2 levels low, thus allowing Fzd3 processing and insertion into the growth cone membrane.
For this to be compatible with the observed expression of Fzd3 and the regulation of responsiveness of post- versus pre-crossing axons, only canonical Shh signalling but not Src family kinase-mediated Shh signalling is expected to regulate Shisa2.
Fzd3 expression is also regulated by calsyntenin 1, which is a type I transmembrane protein that belongs to the cadherin superfamily of proteins. The calsyntenin 1-dependent regulation of vesicle trafficking was identified as a mechanism to keep Fzd3 off the growth cone membrane in pre-crossing axons Alther et al.
Calsyntenin 1 also regulates Robo1 surface expression, suggesting that both Slit sensitivity and sensitivity to Wnts are regulated by trafficking rather than transcription or translation.
This is in contrast to sensitivity to Shh; the difference in responsiveness between pre- and post-crossing axons involves transcriptional regulation of Shh receptors on post-crossing axons Bourikas et al. Irrespective of the underlying mechanism, both the response to midline repellents and the sensitivity to morphogen gradients need to be timed precisely, as only post- but not pre-crossing axons are allowed to respond, or need to respond in a different manner, respectively.
The surprisingly large number of axon guidance cues and receptors required for midline crossing and rostral turning of dI1 commissural axons raises the question of how the navigation of more complex circuits in the brain are regulated.
Are similar guidance mechanisms involved? Class-3 semaphorins and neuropilins are involved in the regulation of midline crossing at the chiasm Erskine et al. Morphogens also contribute to axonal navigation in the brainstem Fenstermaker et al. All these studies confirm that the same molecular mechanisms are involved in the establishment of neural circuits throughout the nervous system.
In turn, this means that the regulation of the different signalling pathways and the temporal and spatial coordination of the different guidance cues and receptors at choice points are likely to be even more complex in the brain. Axon guidance within the brain. The guidance cues that are involved in the navigation of dI1 commissural axons are conserved; they are used during the projection of thalamocortical axons from the different nuclei of the thalamus blue through corridor cells green to the cortex, and by cortical neurons forming the corpus callosum.
Similarly, these guidance cues are involved in the wiring of the visual system and the formation of the optic chiasm. References not mentioned in the main text for cortical axons: Hutchins et al. Indeed, recent studies have identified a number of links between these and other guidance cues during axonal navigation see Table 1. Robo receptors act to expel axons from their intermediate target, the CNS midline, which expresses Slits.
The Class-3 semaphorin Sema3B, which is expressed by the floor plate and mediates its repulsive effect via a receptor complex formed by Npn-2 and plexin A1, is also required for midline crossing Nawabi et al.
Recent studies have identified a link between these two repulsive signalling pathways: plexin A1 was shown to also bind to Slit Delloye-Bourgeois et al. The proteolytic cleavage of Slit was further analysed in flies Alavi et al. This study demonstrated that Robo1 prefers full-length Slit as a ligand in the absence of Dscam, but the cis complex between Dscam1 and Robo1 binds N-Slit in preference. Thalamocortical axons have been shown to be deflected along the rostro-caudal axis depending on the expression of FLRT3.
For example, the co-expression of FLRT3 and Robo1 in rostral thalamocortical axons increases the levels of the netrin receptor Dcc see Box 2 on their growth cones in a protein kinase A-dependent manner. Therefore, these axons are attracted rostrally by parallel gradients of Slit1 and netrin 1 Bielle et al. The observed difference in axonal behaviour in the presence of either netrin or Slit, in comparison with the combination of the two cues, has been corroborated in vitro Dupin et al.
Dcc was identified as the receptor mediating the long-range attractive response to netrin in the spinal cord Keino-Masu et al. However, Dcc has also been shown to mediate an inhibitory response to the long-range repellent Draxin Ahmed et al.
However, these findings were questioned in a recent study demonstrating that Dscam knockout mice do not have any pathfinding errors in the spinal cord Palmesino et al. Furthermore, the netrin-dependent exit of retinal ganglion cell axons from the eye was not affected by the absence of Dscam, although axon fasciculation and their growth from the chiasm to the target was perturbed due to aberrant growth speed Bruce et al. Further support for a link between Robo-Slit and netrin-Dcc signalling has been provided by a recent study of the divergent Robo receptor Robo3 Zelina et al.
This study showed that the presence of netrin results in the phosphorylation of Robo3, which in turn is required for axonal growth to the floor plate. Netrin was found not to bind to Robo3, however, but rather to Dcc, which interacts with Robo3 in cis. Interestingly, the role of Robo3 differs between mammals and non-mammalian vertebrates Zelina et al. In mouse, Robo3 has been shown to affect midline crossing of dI1 commissural axons in the spinal cord Sabatier et al.
One model suggests that Robo3 exists as two splice variants with different expression patterns. In this model, Robo3. Although it is unclear how the change in splice isoforms is regulated, it has been shown that axonal contact with the floor plate triggers local translation of Robo3. Cooperation of guidance cues has also been identified for netrin and Shh in vertebrates Sloan et al. Netrin was also found to synergize with ephrin in the activation of Src family kinase signalling during muscle innervation by motoneurons Poliak et al.
Crosstalk between Shh and Sema3 signalling during midline crossing has also been reported Parra and Zou, In particular, it was shown that exposure of pre-crossing commissural axons to Shh made them sensitive to the repellent effect of the class-3 semaphorins Sema3B and Sema3F, thus explaining the repulsive effect on post-crossing axons observed in vitro and in vivo Zou et al.
Overall, these findings highlight that a great deal of cooperation and crosstalk occurs between various guidance cues and receptors. These studies also demonstrate how important it is to take the complexity of the developing nervous system into account; in vitro experiments looking at a single molecule are likely to miss important aspects of axonal navigation that are influenced by crosstalk between different molecules.
After reaching a choice point, growth cones need to change their surface receptors to be prepared for the next stage of their trajectory. Such changes are possible by different mechanisms.
As I summarize below, studies have demonstrated that all of these possibilities appear to be used by navigating axons Fig. Axon guidance at choice points. A-C Regulation of the surface expression of guidance receptors on growth cones is achieved by precisely orchestrated processes. When a growth cone reaches a choice point, or intermediate target, it needs to change the guidance receptors expressed on its surface in order to change its responsiveness from attraction to repulsion and to be prepared for the next stage of its journey.
Changes can be made at different levels, including within the cell body A , the axon B or the growth cone C. A Changes can occur at the level of gene transcription in the nucleus, followed by mRNA translation in the cell soma.
Translation can be further regulated by miRNAs, thus the presence of an mRNA does not necessarily predict protein synthesis. B Proteins synthesized in the cell body are transported through the axon to the growth cone by anterograde vesicle transport mediated by kinesin motors.
Conversely, retrograde vesicular transport mediated by dynein motors is responsible for signal transport from the growth cone to the cell body. Proteins synthesized in the cell body can also be transported and inserted into the plasma membrane in a precisely controlled manner, because of the selection of specific vesicles by cargo adaptor proteins. These vesicles can then fuse upon a specific trigger derived from growth cone-target interaction 2. Protein levels on growth cones can also be controlled by specific proteases, which in turn can be regulated specifically by cell-cell interactions 3.
Finally, interactions between guidance receptors and guidance cues can be prevented or modulated by cis interactions between molecules in the plane of the growth cone membrane 4. These interactions can be between two identical homophilic or two different heterophilic proteins. Depending on the interaction partner in cis, the affinity for trans interaction partners is set differently.
Analyses of temporal and spatial expression patterns demonstrate that initiation of the expression of guidance receptors very often coincides with the arrival of axons at a choice point for example, Andermatt et al. The signals triggering this change in transcription, however, are mostly unknown Fig. One possibility is a time-dependent mechanism — an intrinsic timer that changes the gene expression programme of a neuron depending on its age.
This would mean that the growth cone changes its surface receptors independently of its environment and its position along the trajectory. Therefore, changes in growth speed would interfere with axon guidance as the encountered guidance cues and their receptors would be out of synchrony.
Evidence for an effect of growth speed, and an internal timing mechanism of gene expression has been found in the visual system for responsiveness to netrin Shewan et al. Although it is unclear how time is counted by a neuron, a mechanism that has been suggested involves accumulation of the adaptor proteins Kaplan et al.
High levels of were suggested to change the attractive effect of Shh into repulsion. On its own, however, the accumulation of an adaptor protein may not be a solid regulator of axonal behaviour.
A more robust mechanism that has been proposed involves a contact-dependent switch: the contact between a growth cone and its intermediate target could induce a transcriptional change in the neuron and thus result in the insertion of guidance receptors in a precisely timed manner. This has been demonstrated for the switch in responsiveness to Shh based on in vivo experiments.
Shh itself was found to trigger the expression of Hhip, its receptor on post-crossing axons, in a glypican 1-dependent manner Bourikas et al.
The released intracellular domain is then transferred to the nucleus to induce the expression of Commissureless, which in turn regulates the expression of Robo on post-crossing axons at the post-translational level see below and, thus, controls sensitivity to Slit during midline crossing Keleman et al. Regulation of the surface expression of guidance receptors is not necessarily dependent on changes in gene transcription; changes in translation can also play a key role Fig.
It had also previously been demonstrated that the sensitivity of retinal ganglion cell axons to the repellent Sema3a is regulated by translational control of Neuropilin 1 expression in a microRNA miRNA -dependent manner Baudet et al.
A role for miRNAs in axonal connectivity in the visual system was suggested previously by the perturbation of the miRNA processing pathway component Dicer1 Pinter and Hindges, Since then, miRNAs have been shown to not only regulate the expression of guidance receptors in the cell body but also regulate protein synthesis locally in the growth cone reviewed by Rajman and Schratt, For example, Slit2-mediated control of growth cone behaviour was recently shown to involve miRNA-mediated transcriptional regulation of cofilin-1, a protein that modulates actin dynamics Bellon et al.
The importance of local translation in growth cones was in fact reported many years ago Campbell and Holt, In recent years, however, a number of guidance cues and receptors have been shown to be translated locally within growth cones.
For example, netrin was shown to regulate the local translation of its receptor Dscam in growth cones Jain and Welshhans, and to affect Dcc-mediated translation Tcherkezian et al. Local synthesis in growth cones at the spinal cord midline has also been described for EphA2 Brittis et al. The local translation of proteins in growth cones depends on transport of mRNAs into the distal axon Fig. The surface expression of active guidance receptors has also been shown to be regulated by specific trafficking and processing, and by interactions with other proteins Fig.
The specific delivery of guidance receptors can thus be used to regulate responsiveness to a particular guidance cue in a temporal manner. For instance, the insertion of Robo1 into the growth cone surface during midline crossing was shown to depend on vesicular trafficking regulated by calsyntenin 1 and Rab GDP dissociation inhibitor RabGDI Alther et al. Calsyntenin 1, but not RabGDI, is also required for the regulation of frizzled 3-mediated post-crossing commissural axon guidance.
The surface insertion of Robo3 receptors in flies is increased by co-expression of the receptor protein tyrosine kinase RPTP69D Oliva et al.
In addition to regulated membrane insertion of guidance receptors, the opposite — the selective removal or shedding of guidance receptors — has also been found Fig. Regulation of ADAM-mediated receptor shedding has been characterized in particular detail in the CNS and involves leucine-rich repeats and immunoglobulin-like domains 2 Lrig2; van Erp et al. Interactions between guidance receptors in the plane of the membrane cis interactions can also modulate their activity at choice points Fig.
The best-studied example of this, which involves cis interaction-dependent attenuation of signalling, occurs during the innervation of the tectum by retinal ganglion cell axons. In this context, repulsive signalling is fine-tuned by cis interactions between EphA receptors and ephrin A ligands on the growth cone surface Suetterlin and Drescher, ; Fiederling et al.
Similarly, shedding of the EphA4 extracellular domain as an alternative regulatory mechanism to cis attenuation is required for proper limb innervation Gatto et al. Fine-tuning of axonal responsiveness can also be achieved via cis interactions of guidance receptors that modulate the binding affinity to molecules on other membranes trans-interactions.
An example of this type of regulation was found for class-6 semaphorins and plexin A receptors. A role for class-6 semaphorins was initially described for the formation of thalamocortical connections Leighton et al. Although they are transmembrane proteins, they were initially considered to act as ligands for plexin A receptors. Today, however, it is clear that class-6 semaphorins have dual functions, acting as ligands in some contexts but also as receptors in others Jongbloets and Pasterkamp, ; Pasterkamp, Sema6A, for instance, acts as a receptor in boundary cap cell precursors Mauti et al.
Several studies have shown that the signalling activities and interactions of class-6 semaphorins are regulated by a complex combination of cis- and trans-interactions with plexin A receptors Haklai-Topper et al. A role for membrane-bound Semaphorin 1a has also been shown for midline crossing in invertebrates, although in this case the effect was found to be independent of Plexin binding Hernandez-Fleming et al.
The cis interaction-mediated regulation of signalling downstream of guidance receptors has been identified as an important mechanism of axon pathfinding in many contexts. Initially, the importance of cis interactions in the modulation of trans interactions was shown for cell adhesion molecules of the immunoglobulin superfamily of cell adhesion molecules IgSF-CAMs; Kunz et al.
More recent studies have confirmed this for commissural axons Niederkofler et al. As I have highlighted here, our knowledge of neural circuit formation in the brain is still very much in its infancy. We can infer molecular mechanisms from what we have learned in one system to another but there is still not a single population of axons for which we have a complete understanding of the molecular mechanisms of navigation to the final target. Because CMM are a symptom in a number of neurological syndromes that are likely to have mutations at multiple genetic loci, it has remained unclear which genetic mutations specifically result in CMM.
These mutations are predicted to result in either a truncated form of the receptor that cannot bind netrin1 [ ], or a form that prevents DCC dimerization [ ], resulting in its degradation by nonsense-mediate mRNA decay [ ]. These studies also proposed that DCC mutations produce mirror movements because of inappropriate ipsilateral CST projections from the hindbrain [ , ].
However, exome sequencing studies have now identified three variants of NTN1 in members of two unrelated families and an unaffiliated individual with CMM. The three variants, which include two missense mutations CysSer and CysArg and one in-frame deletion Iledel , all localize to the netrin NTR domain found at the C-terminus of the protein. Through molecular modeling software Cys is predicted to be important for the formation of disulfide bridges, while Ile is part of a beta strand [ ].
In these cases, CMM appears to be a direct result of NTN1 disruption and not a secondary consequence of a neurological syndrome. The patients do not have other observable neurological defects or mutations in any of the genes previously associated with CMM [ , ]. A tractography analysis of the CST in the NTN1 patients demonstrated that they have an increased proportion of ipsilateral CST projections compared to control subjects [ ], suggesting a role for netrin1 regulating axons crossing the CST midline.
In vitro studies have suggested that the mutant NTN1 allele affects the localization and processing of netrin1 for secretion from the cell. HEK and Hela cell cultures were transfected with either the control or mutated allele of NTN1 , cells were cultured, the supernatant was collected and the cells were lysed to collect the intracellular fraction [ ].
A higher proportion of netrin1 was found in the intracellular fraction in the mutant cultures compared to controls. Together, these studies suggest that the NTN1 exon 7 mutation reduces the level of netrin1 in the extracellular matrix, thereby leading to reduced or aberrant crossing of axons in the CST, resulting in CCM. Axon guidance studies have suggested a model in which developing axons traverse a sequence of intermediate targets during development. Navigating these intermediate targets requires that developing axons respond to extracellular attractive and repulsive guidance cues, including members of the netrin and slit families, which are provided by specialized populations of cells that reside along the axonal trajectory.
Commissural neuron midline crossing has provided a valuable model for the study of axon traversal at the CNS midline intermediate target and has revealed evolutionarily conserved molecular mechanisms that underlie axon guidance. Interestingly, theories of decussation have suggested that midline crossing may have been evolutionarily selected for based on its property to minimize wiring errors during development, suggesting that axon guidance studies at the CNS midline may reveal some of the fundamental aspects of CNS development and organization.
Of particular interest is the fundamental property of how commissural axons regulate their responsiveness to axon guidance cues so that developing axons appropriately extend from one intermediate target to the next without stalling or recrossing previous targets.
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PLoS One. UNC-5, a transmembrane protein with immunoglobulin and thrombospondin type 1 domains, guides cell and pioneer axon migrations in C. The mouse rostral cerebellar malformation gene encodes an UNClike protein.
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