Plexin/neuropilin complexes mediate repulsion by the axonal guidance signal semaphorin 3A

In the developing nervous system axons navigate with great precision over l arge distances to reach their target areas. Chemorepulsive signals such as the semaphorins play an essential role in this process. The effects of one of these repulsive cues, semaphorin 3A (Sema3A), are mediated by the membra ne protein neuropilin-1 (Npn-l). Recent work has shown that neuropilin-1 is essential but not sufficient to form functional Sema3A receptors and indic ates that additional components are required to transduce signals from the cell surface to the cytoskeleton. Here we show that members of the plexin f amily interact with the neuropilins and act as co-receptors for Sema3A. Neu ropilin/plexin interaction restricts the binding specificity of neuropilin- 1 and allows the receptor complex to discriminate between two different sem aphorins. Deletion of the highly conserved cytoplasmic domain of Plexin-A1 or -A2 creates a dominant negative Sema3A receptor that renders sensory axo ns resistant to the repulsive effects of Sema3A when expressed in sensory g anglia. These data suggest that functional semaphorin receptors contain ple xins as signal-transducing and neuropilins as ligand-binding subunits. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.