Plexin-A4-dependent retrograde semaphorin 3A signalling regulates the dendritic localization of GluA2-containing AMPA receptors

Abstract

The dendritic targeting of neurotransmitter receptors is vital for dendritic development and function. However, how such localization is established remains unclear. Here we show that semaphorin 3A (Sema3A) signalling at the axonal growth cone is propagated towards the cell body by retrograde axonal transport and drives AMPA receptor GluA2 to the distal dendrites, which regulates dendritic development. Sema3A enhances glutamate receptor interacting protein 1-dependent localization of GluA2 in dendrites, which is blocked by knockdown of cytoplasmic dynein heavy chain. PlexinA (PlexA), a receptor component for Sema3A, interacts with GluA2 at the immunoglobulin-like Plexin-transcription-factor domain (PlexA-IPT) in somatodendritic regions. Overexpression of PlexA-IPT suppresses dendritic localization of GluA2 and induces aproximal bifurcation phenotype in the apical dendrites of CA1 hippocampal neurons. Thus, we propose a control mechanism by which retrograde Sema3A signalling regulates the glutamate receptor localization through trafficking of cis-interacting PlexA with GluA2 along dendrites.

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

“…In addition, local treatment by monodancylcadaverin, an inhibitor of clathrin-dependent endocytosis, at the distal axon suppressed growth cone and distal axon distribution of venus-tagged Sema3A. 53 These findings further suggest active and physiological roles of the semaphorin in stimulating endocytosis of the growth cone plasma membrane, 54,55 and the Sema3A receptor complex is retrogradely transported through tetrodotoxin-and nimodipine-sensitive signaling along the axon. However, as described above, tetrodotoxin suppressed the accele ration of axonal transport but not the growth cone collapse induced by Sema3A.…”

“…Such a polarized responsiveness to Sema3A is similarly observed in hippocampal neurons. 53 Importantly, tetrodotoxin, which blocks voltage-dependent sodium channels, suppressed the acceleration of axonal transport but not the growth cone collapse induced by Sema3A. 54,55 Likewise, K252a, a tropomyosin receptor kinase A (TrkA) inhibitor, or TrkA knockdown suppressed the Sema3A-induced acceleration of axonal transport but did not affect the growth cone collapse (see below).…”

“…Sema3A induced dendritic transport as well as axonal transport, with the peak effect on dendrites lagging behind that on axons. 53 Furthermore, Sema3A that was locally applied to axonal growth cone induced axonal and dendritic transport. This finding suggests that local signaling of Sema3A at the axonal growth cones may be propagated to cell body and/or dendrites, thereby inducing dendritic transport.…”

“…54,55 Thus calcium ions are involved in regulating both growth cone morphology and axonal transport, but sodium ions are involved only in Sema3A-induced axonal transport. 53,54 The coupling mechanism upon Sema3A stimulation between Ca 2C channels and Na C channels is unknown. Although several L-type Ca 2C channel blockers suppress Sema3A-induced axonal transport, 54,55 the voltage-dependent Ca 2C channels that mediate Sema3A response may include R-type Ca 2C channels, as demonstrated in Xenopus spinal neurons, 64 and in embryonic day 15 (E15) mouse DRG.…”

“…When Sema3A was locally applied to axonal areas, but not to somatodendritic areas, it increased the immunostaining of GluA2 in the dendrites, suggesting that Sema3A signaling propagates from the axonal growth cone and induces the dendritic localization of GluA2. 53 If the site of Sema3A action is localized in the axonal growth cone area, how was this retrograde Sema3A signaling propagated to cell bodies and/or dendrites? One possible mechanism is a dynein-dependent retrograde axonal transport.…”