Molecular basis of semaphorin-mediated axon guidance

The semaphorin family of proteins constitute one of the major cues for axon al guidance. The prototypic member of this family is Sema3A, previously des ignated semD/III or collapsin-1. Sema3A acts as a diffusible, repulsive gui dance cue in vivo for the peripheral projections of embryonic dorsal root g anglion neurons. Sema3A binds with high affinity to neuropilin-1 on growth cone filopodial tips. Although neuropilin-1 is required for Sema3A action, it is incapable of transmitting a Sema3A signal to the growth cone interior , Instead, the Sema3A/neuropilin-1 complex interacts with another transmemb rane protein, plexin, on the surface of growth cones. Certain semaphorins, other than Sema3A, can bind directly to plexins. The intracellular domain o f plexin is responsible for initiating the signal transduction cascade lead ing to growth cone collapse, axon repulsion, or growth cone turning. This i ntracellular cascade invoices the monomeric G-protein, Rac1, and a family o f neuronal proteins, the CRMPs, Rac1 is likely to be involved in semaphorin -induced rearrangements of the actin cytoskeleton, but how plexin controls Rac1 activity is not known. Vertebrate CRMPs are homologous to the Caenorha bditis elegans unc-33 protein, which is required for proper axon morphology in worms. CRMPs are essential for Sema3A-induced, neuropilin-plexin-mediat ed growth cone collapse, but the molecular interactions of growth cone CRMP s are not well defined. Mechanistic aspects of plexin-based signaling for s emaphorin guidance cues may have implications for other axon guidance event s and for the basis of growth cone motility, (C) 2000 John Wiley & Sons, In c.