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The semaphorin family includes both transmembrane and secreted proteins that have been shown to function as axon repulsion cues in multiple systems. Neuropilins were recently identified as the receptors for secreted semaphorins: neuropilin-1 (Npn-1) is a receptor for Sema3A (semaphorin III) and neuropilin-2 (Npn-2) is a receptor for Sema3F (semaphorin IV). Sema3C (Semaphorin E) can bind to both of the neuropilins with the same affinity in viro. Little is known, however, about the mechanisms by which ligand-receptor interactions exert their repulsive effect, and their roles curing patterning of projections of the developing nervous system. Previous studies revealed a complementary expression pattern between Sema3F and Npn-2. Especially interesting is that in the periphery, Sema3F is strongly expressed in organs that receive sympathetic innervation, whereas Npn-2 is expressed highly in the sympathetic neurons including those whose cell bodies are within the superior cervical ganglion (SCG), postganglionic neurons in the sympathetic chain, and distinct peripheral plexuses. The studies outlined in this proposal will further characterize the specific interactions between Npn-2 and the known secreted semaphorins, as well as to define their roles in axonal pathfinding and target recognition in the developing sympathetic nervous system. First, whether Npn-2 serves as a functional receptor for other secreted semaphorins will be determined by an in viro repulsion assay using SCGs either treated with Npn-1 functional blocking antibodies, isolated from Npn-2 -/- mice, or a combination of these two. Second, the spatial and temporal patterns of expression of secreted semaphorins will be defined by in situ hybridization, and a detailed Npn-2 protein expression pattern will be examined by immunocytochemical staining using anti-Npn-2 antibodies. Finally, the requirement for Npn-2 in sympathetic innervation of targets will be assessed using recently generated Npn-2 -/- mice. A particular emphasis will be placed on the identification of innervation defects in a series of target organs by Tyrosine Hydroxylase (TH) and catecholamine histofluorescence techniques. As a whole, results from these in viro and in vivo analyses will provide a better understanding of the roles played by Sema3B, 3C, 3E, 3F and Npn-2 in sympathetic target innervation, and how specific semaphorin-neuropilin interactions control axon guidance and development of the sympathetic nervous system.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.