A functional coupling between CRMP1 and Na_v1.7 for retrograde propagation of Semaphorin3A signaling

Semaphorin3A (Sema3A) is a secreted type of axon guidance molecule that regulates axon wiring through complexes of neuropilin-1 (NRP1) with PlexinA protein receptors. Sema3A regulates the dendritic branching through tetrodotoxin (TTX)-sensitive retrograde axonal transport of PlexA proteins and tropomyosin-related kinase A (TrkA) complex. We here demonstrate that Na_v1.7 (encoded by SCN9A), a TTX-sensitive Na⁺ channel, by coupling with collapsin response mediator protein 1 (CRMP1), mediates the Sema3A-induced retrograde transport. In mouse dorsal root ganglion (DRG) neurons, Sema3A increased co-localization of PlexA4 and TrkA in the growth cones and axons. TTX treatment and RNAi knockdown of Na_v1.7 sustained Sema3A-induced colocalized signals of PlexA4 and TrkA in growth cones and suppressed the subsequent localization of PlexA4 and TrkA in distal axons. A similar localization phenotype was observed in crmp1 DRG neurons. Sema3A induced colocalization of CRMP1 and Na_v1.7 in the growth cones. The half maximal voltage was increased in crmp1 neurons when compared to that in wild type. In HEK293 cells, introduction of CRMP1 lowered the threshold of co-expressed exogenous Na_v1.7. These results suggest that Na_v1.7, by coupling with CRMP1, mediates the axonal retrograde signaling of Sema3A.