Semaphorin3A (Sema3A) is a secreted type of repulsive axon guidance molecule that has an important role in neuronal network formation and axon guidance. Sema3A facilitates axonal transport through tetrodotoxin (TTX)-sensitive Na+ channels. However, how the Sema3A-induced signalling event is propagated through these ion channels to the cell body is unknown. In their study on page 1393, Naoya Yamashita, Yoshio Goshima and colleagues identify the molecular mechanism of TTX-sensitive propagation of retrograde Sema3A signalling. Sema3A is shown to induce clathrin-dependent colocalisation of PlexA4 and TrkA in the growth cones and axons of mouse dorsal root ganglion neurons. Next, the authors demonstrate that TTX, a voltage-dependent Na+ channel blocker, sustains this Sema3A-induced colocalisation of PlexA4 and TrkA in the growth cones, and identify Nav1.7 as the voltage-dependent Na+ channel responsible for sustaining the colocalisation. Moreover, there is a functional coupling between Nav1.7 and the intracellular mediator protein CRMP1, but not CRMP2, in inducing retrograde transport of PlexA4 and TrkA from growth cones to axons. The authors therefore propose that the axonal retrograde signalling of Sema3A requires functional coupling between Nav1.7 and CRMP1.
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