Key Points
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Neuronal migration and axon pathfinding are guided by extracellular cues, including netrins, semaphorins, ephrins and Slits. This review focuses on the signalling mechanisms that underlie axon guidance and neuronal migration in the vertebrate nervous system.
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There are several classical models of axon projection and neuronal migration in vertebrates, including the retinotectal projection, the commissural axons of the spinal cord, the radially migrating neuronal precursors in the neocortex, and the tangentially migrating neurons in the rostral migratory stream.
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Actin assembly is a key process that controls the growth and steering of axon growth cones (although recent evidence also supports a role for microtubules). The Rho family of small GTPases, which includes Rho, Rac and Cdc42, have important roles in regulating actin cytoskeletal dynamics and have been implicated in growth cone guidance.
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Netrins were the first family of directional guidance cues to be found in both invertebrate and vertebrate nervous systems. Netrin-1 and netrin-2 were identified as floor-plate-derived promoters of commissural axon outgrowth. A single netrin can be attractive to some axons and repulsive to others.
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Semaphorins are a family of secreted and membrane-associates proteins that can mediate axon repulsion and growth cone collapse. They have also been implicated in immune responses.
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Ephrins are membrane-associated guidance molecules, and are divided into two classes (A and B) on the basis of their mechanism of membrane association. The Eph proteins were originally defined as the receptors for the ephrins, but they can also act as ephrin ligands.
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Slits are axon repellents, and they are also important for neuronal migration. Roundabout (Robo) is a cell surface receptor that is responsible for the repulsive effect of Slit.
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The chemokine stromal-derived factor 1 (Sdf1) is involved in axon guidance and neuronal migration. Sdf1 is expressed in the meninges surrounding the cerebellum, and it prevents premature migration of granule cells into the inner layer by anchoring them in the external layer.
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Recent reports have implicated several well-known morphogens in axon guidance, including sonic hedgehog, bone morphogenetic proteins and the Wnt family of secreted proteins.
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Different signals have to be integrated in the growth cone to reach an appropriate response and this requires crosstalk between the signalling pathways; for example, through receptor–receptor interaction, regulation of the RhoGTPases or modulation of intracellular levels of second messengers.
Abstract
Several families of extracellular guidance cues have been implicated in guiding neurons and axons to their appropriate destinations in the nervous system. Their receptors include single- and seven-transmembrane receptors, and their signal transduction pathways converge onto the Rho family of small GTPases, which control the cytoskeleton. A single guidance protein can use different mechanisms to regulate different kinds of motility or the motilities of different cell types. There is crosstalk between the signalling pathways initiated by distinct guidance cues. Studies of neuronal guidance mechanisms have shed light not only on neural development, but also on other processes that involve the extracellular regulation of the cytoskeleton.
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Acknowledgements
Our review is limited by space, and work in invertebrates is covered more extensively in the reivew by Araújo and Tear in the November issue of Nature Reviews Neuroscience. The authors wish to thank J. Aurandt, H. Jiang, R. Kruger and H. Vikis for critical reading of the manuscript, G. Liu for help with figure 1e, M. Ward for the colour panel in figure 2 and for the neuronal migration panels in box 1, X.-B. Yuan for the axon turning panels in box 1, H.-T. Park for help with table 1. Research in our laboratories has been supported by grants from the NIH (K.L.G and Y.R.), the Walther Cancer Institute (K.L.G.) and the National Brain Tumor Foundation (Y.R).
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Glossary
- ANGIOGENESIS
-
The formation of blood vessels, such as occurs during embryogenesis, tissue repair or tumourigenesis.
- GLYCOSYLPHOSPHATIDLYLINOSITOL LINKAGE
-
A molecular mechanism for attaching a cell membrane protein to the lipid bilayer. It consists of a glycerophospholipid molecule that is attached to the protein through a carbohydrate chain.
- BONE MORPHOGENETIC PROTEINS
-
Multifunctional secreted proteins of the transforming growth factor-β superfamily. In the early embryo, they participate in dorsoventral patterning.
- WNT PROTEINS
-
A family of highly conserved secreted signalling molecules that are related to the Drosophila wingless protein, and which regulate cell–cell interactions during embryogenesis. Wnt proteins bind on the cell surface to receptors of the Frizzled family.
- TECTUM
-
The dorsal portion of the midbrain (mesencephalon) that mediates reflexive responses to visual and auditory stimuli.
- OPTIC CHIASM
-
The crossing point, in the base of the forebrain, for fibres from the two optic stalks that project to the opposite side of the brain.
- FLOOR PLATE
-
The neural tube has been divided into different regions. The ventral cells closest to the midline constitute the floor plate. The dorsal cells closest to the midline correspond to the roof plate. The alar plate (dorsal) and the basal plate (ventral) lie between these two cell populations and are separated by the sulcus limitans.
- MICROTUBULES
-
Hollow tubes, 25 nm in diameter, formed by the lateral association of 13 protofilaments, which are themselves polymers of α- and β-tubulin subunits.
- LIM
-
Cysteine- and histadine-rich domain that was originally defined by lin1, isl1 and mec3.
- SH3 DOMAIN
-
Src-homology domains are involved in interactions with phosphorylated tyrosine residues on other proteins (SH2 domains) or with proline-rich sections of other proteins (SH3 domains).
- DEATH DOMAIN
-
A protein–protein interaction domain found in many proteins that are involved in signalling and apoptosis.
- CASPASES
-
A family of intracellular cysteine endopeptidases that have a key role in inflammation and mammalian apoptosis. They cleave proteins at specific aspartate residues.
- PROTEASOME
-
A protein complex responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.
- PDZ DOMAIN
-
A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. It can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains.
- INTEGRINS
-
A large family of heterodimeric transmembrane proteins that act as receptors for cell adhesion molecules.
- EXPRESSION CLONING
-
Cloning strategy that is based on the transfection of cDNAs such that functional proteins are expressed, followed by a screening of the functional activity of the gene of interest.
- DOMINANT NEGATIVE
-
A mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.
- NOTOCHORD
-
A rod-like structure of mesodermal origin that is found in vertebrate embryos. It participates in the differentiation of the ventral neural tube and in the specification of motor neurons.
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Guan, KL., Rao, Y. Signalling mechanisms mediating neuronal responses to guidance cues. Nat Rev Neurosci 4, 941–956 (2003). https://doi.org/10.1038/nrn1254
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DOI: https://doi.org/10.1038/nrn1254
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