Semaphorin 6B acts as a receptor in post-crossing commissural axon guidance

Abstract

Semaphorins are a large family of axon guidance molecules that are known primarily as ligands for plexins and neuropilins. Although class-6 semaphorins are transmembrane proteins, they have been implicated as ligands in different aspects of neural development, including neural crest cell migration, axon guidance and cerebellar development. However, the specific spatial and temporal expression of semaphorin 6B (Sema6B) in chick commissural neurons suggested a receptor role in axon guidance at the spinal cord midline. Indeed, in the absence of Sema6B, post-crossing commissural axons lacked an instructive signal directing them rostrally along the contralateral floorplate border, resulting in stalling at the exit site or even caudal turns. Truncated Sema6B lacking the intracellular domain was unable to rescue the loss-of-function phenotype, confirming a receptor function of Sema6B. In support of this, we demonstrate that Sema6B binds to floorplate-derived plexin A2 (PlxnA2) for navigation at the midline, whereas a cis-interaction between PlxnA2 and Sema6B on pre-crossing commissural axons may regulate the responsiveness of axons to floorplate-derived cues.

Calsyntenin 1-mediated trafficking of axon guidance receptors regulates the switch in axonal responsiveness at a choice point

“…In contrast to Robo1 and RabGDI, loss of calsyntenin 1 had an additional effect on post-crossing commissural axons. Like Shh (Bourikas et al, 2005;Wilson and Stoeckli, 2013), Wnts (Domanitskaya et al, 2010;Avilés and Stoeckli, 2016), SynCAMs (Niederkofler et al, 2010) and semaphorin 6B (Andermatt et al, 2014), calsyntenin 1 was required for the rostral turning of postcrossing commissural axons. Our detailed in vivo analyses indicate a regulatory role of calsyntenin 1-mediated trafficking in midline crossing by controlling Robo1 expression and in longitudinal axon guidance by controlling frizzled 3 expression.…”

Commissural axon navigation: Control of midline crossing in the vertebrate spinal cord by the semaphorin 3B signaling

“…Specific knockdown of FP-PlexinA2 also resulted in stalling, as did so the specific knock-down of Sema6B, which is endogenously expressed in commissural neurons. Thus, this identified a first signaling for crossing and post-crossing commissural axons arising from Sema6B acting as a commissural receptor for FP-PlexinA2, acting non-cell autonomously as a ligand 1 . In addition, PlexinA2 over-expression in pre-crossing commissural neurons strongly altered their ability to reach the FP, a phenotype that was interpreted as resulting from oversensitivity to ventral spinal cord/FP repellents.…”

“…Indeed, first, not only Nrp2 but also PlexinA1 is expressed by both commissural axons and FP glial cells. Second as shown in the chick embryo for PlexinA2, 1 FP-PlexinA1 could have non cell autonomous functions. Thus, a key experiment would be to test which of commissural- or FP-specific PlexinA1 deletion rescues the ventral commissure thickness in context of FP-Nrp2 deletion.…”

“…dl1 commissural neurons, specified by Lhx2/9 transcription factors, 44 elaborate a typical pattern of axonal projections, whose navigation has been widely investigated. The axons extend ventrally toward the FP, cross the midline, exit the FP and turn rostrally to ascend toward supraspinal levels, to convey proprioceptive information to the cerebellum 1 . The generation of transgenic mice expressing LacZ or GFP under the control of the Math1 promotor has allowed a precise spatial and temporal mapping of commissural dl1 axon navigation in the mouse embryo.…”

“…Second in the chick embryo, a recent study investigated the PlexinA/Semaphorin signaling during spinal commissural axon guidance 1 . PlexinAs were noted to have dynamic spatio-temporal expression patterns, with some members being expressed by commissural axons and FP cells such as PlexinA1 and PlexinA2, and others expressed only by commissural axons such as PlexinA4.…”