TrkA mediates retrograde semaphorin 3A signaling through plexin A4 to regulate dendritic branching

Semaphorin 3A (Sema3A), a secretory semaphorin, exerts various biological actions via a complex between neuropilin-1 and plexin-As (PlexAs). Sema3A induces retrograde signaling, which is involved in regulating dendritic localization of GluA2, an AMPA receptor subunit. Here, we investigated a possible interaction between retrograde signaling pathways for Sema3A and nerve growth factor (NGF). Sema3A induces colocalization of PlexA4 signals with those of tropomyosin-related kinase A (TrkA), in growth cones and these colocalized signals were then observed along the axons. The time-lapse imaging of PlexA4 and several TrkA mutants showed that the kinase and dynein-binding activity of TrkA were required for Sema3A-induced retrograde transport of PlexA4/TrkA complex along the axons. The inhibition of PI3K/Akt signal, a downstream signaling of TrkA, in the distal axon suppressed Sema3A-induced dendritic localization of GluA2. The knockdown of TrkA suppressed Sema3A-induced dendritic localization of GluA2 and that suppressed Sema3A-regulated dendritic branching both in vitro and in vivo. These findings suggest that by interacting with PlexA4, TrkA plays a crucial role in redirecting local Sema3A signaling to retrograde axonal transport, thereby regulating dendritic GluA2 localization and patterning.