Axonal guidance: Molecular mechanisms, biology of neurodevelopment, and a discussion of potential roles in nerve repair

The semaphorins are a diverse family of secreted and transmembrane proteins; most are expressed during development throughout the nervous system and in non-neuronal tissues. Many secreted semaphorins, including the well-characterized semaphorin, Sema3A, can function as repulsive axonal guidance cues. In vitro co-culture experiments have shown that Sema3A functions as a selective repulsive guidance cue, and in vivo genetic studies show that Sema3A plays an essential role in the projection and fasciculation of several populations of axons during development.; We have demonstrated that the axonal glycoprotein neuropilin-1 is a receptor, or a component of a receptor, for Sema3A. Neuropilin-1 is expressed in all known Sema3A-responsive neurons. Neuropilin-1 is the founding member of a gene family, and is 44% identical to neuropilin-2, which has similar domain structure as neuropilin-1. Neuropilin-2 is also expressed in specific populations of neurons during development. Like neuropilin-1, neuropilin-2 is a high affinity binding protein for secreted semaphorins. However, it differs from neuropilin-1 in that it binds Sema3C and Sema3F, but not Sema3A, with high affinity.; To better understand the function of neuropilin-2, we have undertaken an analysis of its expression and role during neurodevelopment. We generated antibodies directed against neuropilin-2 to describe its axonal distribution. In addition, we used these antibodies as function-blocking reagents to determine whether, like neuropilin-1, neuropilin-2 is a receptor for repulsive semaphorin guidance cues. Sema3F, which binds to neuropilin-2 in vitro with high affinity, also binds endogenous receptors located on superior cervical ganglia (SCG) neurons. Neuropilin-2, in addition to neuropilin-1, is expressed on SCG axons. We performed co-culture experiments and found that Sema3F, like Sema3A, repels this population of neurons. In contrast, E15 NGF-responsive dorsal root ganglion neurons, which express neuropilin-1 but not neuropilin-2, were not repelled by Sema3F. Antibody blocking studies have shown that neuropilin-2 is required to mediate Sema3F repulsive guidance in SCG neurons. Neuropilin-2 is, therefore, a functional semaphorin, receptor for secreted semaphorins. The characterization of neuropilins and their selective interactions with semaphorins will contribute to our understanding of the roles played by repulsive guidance cues in central and peripheral neuronal guidance events during development.