Neuropilin-1 extracellular domains mediate semaphorin D/III-induced growthcone collapse

Somatosensory axon outgrowth is repulsed when soluble semaphorin D (semD) b inds to growth cone neuropilin-1 (Npn-1). Here, semD ligand binding studies of Npn-1 mutants demonstrate that the sema domain binds to the amino-termi nal quarter, or complement-binding (CUB) domain, of Npn-1. By herpes simple x virus- (HSV-) mediated expression of Npn-1 mutants in chick retinal gangl ion cells, we show that semD-induced growth cone collapse requires two segm ents of the ectodomain of Npn-1, the CUB domain and the juxtamembrane porti on, or MAM (meprin, A5, mu) domain. In contrast, the transmembrane segment and cytoplasmic tail of Npn-1 are not required for biologic activity. These data imply that the CUB and MAM ectodomains of Npn-1 interact with another transmembrane growth cone protein that in turn transduces a semD signal in to axon repulsion.