Neuropilin receptors guide distinct phases of sensory and motor neuronal segmentation

Abstract

The segmented trunk peripheral nervous system is generated by ventrally migrating neural crest cells that exclusively invade the anterior sclerotome and differentiate into metameric dorsal root and sympathetic ganglia. Meanwhile, ventral spinal motor axons also project through the somites in a segmental fashion. How peripheral nervous system segmentation is generated is unknown. We previously showed that neuropilin 2 (Nrp2)/semaphorin 3F (Sema3F) signaling is required for segmental neural crest migration, but not for metameric dorsal root gangliogenesis. We now expand these results to show that Nrp2 patterns initial motor axon outgrowth as well. Later, Nrp1/Sema3A signaling is essential for segmental dorsal root gangliogenesis and motor axonal fasciculation into ventral roots. Strikingly, Nrp/Sema signaling is not required for sympathetic ganglia segmentation. These data show that Nrp2 and Nrp1 work together to produce segmentation of sensory and motor nerves, and that dorsal peripheral nervous system metamerism is generated in a stepwise, Nrp-dependent process.

A novel role for MuSK and non-canonical Wnt signaling during segmental neural crest cell migration

“…Nrp1/Sema3A signaling repels neural crest cells from the intersomitic space to the sclerotome, and Nrp2/Sema3F signaling functions to restrict neural crest cell migration to the anterior half of the sclerotome (Gammill et al, 2006b;Schwarz et al, 2009a;Schwarz et al, 2009b). Finally, combined loss of Nrp1 and Nrp2 signaling results in perturbation of DRG segmentation, whereas metameric organization of sympathetic ganglia remains unaffected (Roffers-Agarwal and Gammill, 2009). Combined, these studies have established a crucial role for Nrp/Sema signaling in segmental neural crest migration.…”

“…In embryos lacking Nrp2, neural crest cells migrate initially in an unsegmented manner but presumably reorganize and migrate in a segmental fashion at ventral somite levels where sympathetic ganglia form (Gammill et al, 2006b). Moreover, in Nrp1/Nrp2 double mutants, metameric organization of sympathetic ganglia still remains intact (Roffers-Agarwal and Gammill, 2009), suggesting that additional factors, and possibly additional signaling pathways, play a crucial role in keeping neural crest cells restricted to their segmental path. Finally, neural crest cells migrate in close proximity to spinal motor axons, and Nrp1 and Nrp2 are also required for patterned spinal motor axon outgrowth (RoffersAgarwal and Gammill, 2009), consistent with a potential role for motor axons in neural crest cell migration.…”

Mechanisms driving neural crest induction and migration in the zebrafish andXenopus laevis

“…sema3F and 3G are expressed in neural crest-free regions, while and nrp2a and nrp2b are expressed in cranial neural crest cells. 244,245 In zebrafish, mutations in pbx4 is suppressed following knockdown of sema3F/3G and overexpression of sema3Gb permits crest cells to migrate in normally crest cell-free zones. 246 Other genes, such as Disc1, have more recently been show to be involved in cranial neural crest cells migration.…”

Neuropilin, you gotta let me know

“…53 Because SEMA3A/NRP1 and SEMA3F/NRP2 signaling control distinct aspects of NCC guidance, mutants deficient in both pathways display severe defects in NCC guidance that lead to fusion of the dorsal root ganglia. 55,56 The signaling co-receptors for NRP1 and NRP2 in semaphorinmediated NCC guidance have not yet been identified, but they are not PLXNA3 or PLXNA4. 57 Rather, these plexins control sympathetic neuronal patterning, once NCCs have begun to differentiate into neuronal progenitors.…”