Fig. 1. Working models for the role of class 3 semaphorins in mouse vascular development. (A) NRP1 contains several distinct structural domains that cooperate to mediate binding of class 3 semaphorins and VEGF164; the a1 domain is crucial for binding the SEMA domain, the b1 domain for VEGF164 binding. (B) Based on tissue culture models, it has been suggested that SEMA3A modulates VEGF signalling by competing with VEGF164 for binding to NRP1. (C) SEMA3A may signal directly through complexes containing NRP1 and A-type plexins in endothelial cells, as observed in neurons. SEMA3E and possibly other class 3 semaphorins may influence vascular development by signalling through plexin D1-NRP1 complexes (D) and/or through plexin D1 in a mechanism that does not require NRP1 (E). (F) VEGF164 has been implicated as a modifier of neuronal growth and axon guidance based on its ability to compete with SEMA3A for NRP1 binding in a neuronal progenitor cell line in vitro.