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

Abstract

Semaphorin 3A (Sema3A), a secretory semaphorin, exerts various biological actions through a complex between neuropilin-1 and plexinAs (PlexAs). Sema3A induces retrograde signaling, which is involved in regulating dendritic localization of GluA2 (also known as GRIA2), 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 (also known as PLXNA4) signals with those of tropomyosin-related kinase A (TrkA, also known as NTRK1) in growth cones, and these colocalized signals were then observed along the axons. The timelapse 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 the PlexA4-TrkA complex along the axons. The inhibition of the phosphoinositide 3-kinase (PI3K)-Akt signal, a downstream signaling pathway 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.

A functional coupling between CRMP1 and Nav1.7 for retrograde propagation of Semaphorin3A signaling

“…Sema3A-induced axonal transport could play an essential role in mediating some of the biological activities of Sema3A (Goshima et al, 2016;Yamashita et al, 2014Yamashita et al, , 2016c. Sema3A signaling at the axonal growth cone is propagated towards the cell body by retrograde axonal transport and drives the AMPA receptor GluA2 to the distal dendrites, thereby regulating dendritic development .…”

“…Sema3A signaling at the axonal growth cone is propagated towards the cell body by retrograde axonal transport and drives the AMPA receptor GluA2 to the distal dendrites, thereby regulating dendritic development . Sema3A induces dynein-dependent retrograde axonal transport of a tropomyosin kinase A (TrkA)-PlexA4 complex along the axons (Yamashita et al, 2016c). To achieve its biological activity, Sema3A and its signaling complex PlexA4-TrkA must be retrogradely transported along the axon from the growth cone to the cell body.…”

“…However, the kinase and dynein-binding activities of TrkA are required for Sema3A-induced retrograde transport of the PlexA4-TrkA complex. The kinase activity of TrkA is also required for Sema3A to induce dendritic localization of GluA2 and branching since expression of the K537A mutant does not rescue the knockdown effect of TrkA (Yamashita et al, 2016c). In addition, ion signaling plays an essential role in this transport process (Yamane et al, 2012;Yamashita et al, 2016a).…”

Regulation of dendritic development by semaphorin 3A through novel intracellular remote signaling

“…Furthermore, Sema3A induced retrograde transport of both PlexA4 and TrkA, whereas NGF induced the transport of TrkA without modifying that of PlexA4. 86 Moreover, unlike Sema3A, NGF did not induce colocalization of PlexA4 and TrkA. These findings indicate that despite a shared interaction with TrkA, Sema3A and NGF play different biological roles through distinct signaling pathways in developing neurons.…”

“…These findings indicate that TrkA plays a crucial role in mediating Sema3A-induced retrograde signaling by interacting with PlexA4, thus providing a novel mode of crosstalk between the 2 signaling pathways of NGF and Sema3A. 86 Interestingly, the level of phosphorylated Akt was increased at the early phase (5 min), but decreased 30 min after exposure to Sema3A. Thus signaling mechanisms for the initial Akt response might differ from those for the late-phase response to Sema3A.…”