Class 3 secreted semaphorin (Sema3A) is a chemorepellent that acts upon a wide variety of axons. As such, it induces a dramatic redistribution and depolymerization of actin filaments that results in growth cone collapse. Plexins are single pass, transmembrane signaling proteins encompassing Plexin A1, A2, A3 and A4. Plexins form a complex with neuropilin-1 and -2 and the cell adhesion protein L1 to form a functional semaphorin receptor. The GTPase Rnd1 binds to the cytoplasmic domain of Plexin A1 to trigger cytoskeletal collapse. In contrast, the GTPase RhoD blocks Rnd1-mediated Plexin A1 activation and repulsion of sympathetic axons by Sema3A. Neuropilin-1, a single pass transmembrane glycoprotein, was originally identified as a semaphorin receptor mediating axon growth cone collapse. In addition, neuropilin-1 is involved in axonal fasciculation, neuronal migration, dendritic guidance and repair of the adult nervous system. Neuropilin-1 is also an isoform-specific VEGF receptor on tumor and endothelial cells. Loss of neuropilin-1 function causes vascular remodeling and branching defects, which is compounded by additional loss of neuropilin-2 function.
