[Molecular mechanism of axon guidance]

The functioning of the vertebrate brain depends on the differentiation and positioning of the neural cells, and on the specific connections these cells make among themselves and their peripheral targets. Semaphorin3A (Sema3A), a secreted type of guidance cue of the semaphorin family, possesses a strong repulsive activity to a subset of neurons such as dorsal root ganglia and sympathetic neurons. CRMP (collapsin response mediator protein) was originally identified as an intracellular mediator of Sema3A by using Xenopus laevis oocyte expression system, but its mechanism has long been ill-defined. We demonstrate that Fyn-Cdk5 complex acts as a downstream mediator of Sema3A signaling cascades that induce growth cone collapse. In addition, the sequential phosphorylation of CRMP2 by Cdk5 and GSK3beta is an important process of Sema3A signaling. Since the dual-phosphorylated CRMP2 is recognized with the antibody 3F4, a highly reactive antibody with the neurofibrillary tangles of Alzheimer's disease, the same mechanism for Sema3A signaling may have some relevance to the pathological aggregation of the microtubule-associated proteins.