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.

Reverse signaling by Semaphorin-6A regulates cellular aggregation and neuronal morphology

“…Finally, a recent study in the developing spinal cord illustrates a similar scenario, in this case involving Sema6B and PlxnA2 [53]. Commissural neurons express Sema6B, which acts as a receptor for PlxnA2 expressed by the floorplate, with this interaction promoting midline crossing.…”

“…The balance between these various interactions will likely depend on the precise stoichiometry of the proteins and may also be dynamically altered by interactions with additional proteins or newly encountered cells (e.g., ref. 53). Supplementary Figure 1 Figure 3.…”

Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance of KS‐glycodynamics and interactive capability with neuroregulatory ligands

“…Robo's 1-3 have critical roles to play directing the spinal commissural axons as they cross the midline of the main spinal axis(Jaworski et al 2010). The Robo 3 receptor is intimately associated with the development and function of the commissural axons potentiating mid-line attractive forces through interaction with Slit proteins which guide the commissural neurons across the developing spinal cord(Friocourt and Chedotal 2017), a process which is also aided by the semaphorins and in particular semaphorin 3B(Pignata et al 2016) and 6B(Andermatt et al 2014). Morphogenetic factors and a myriad of transcription factors including Wnt and a network of Wnt receptors(Aviles and Stoeckli 2016;Horigane et al 2016) also participate in the guidance of the commissural axons.…”

PKC induces release of a functional ectodomain of the guidance cue semaphorin6A

“…Additionally, Sema6D-expressing cells spontaneously release the Sema6D ectodomain, which is thought to play a role in cardiac development [24,25]. The Sema6 class also has critical functions in nervous system development [11,[26][27][28][29][30]], yet it is currently unknown whether or not a Sema6 protein can produce a soluble variant that is functional in the nervous system. However, in proteomics analyses we and others found evidence for sSemas, including possible variants of Sema6A and Sema6D that were produced in vivo and released into mammalian embryonic cerebrospinal fluid (CSF) or plasma [31][32][33].…”

“…Given that our proteomics analyses identified Sema6A in CSF [31], we were prompted to ask if Sema6A might generate a naturally released ectodomain. This would have important implications as Sema6A could then signal at a distance and could act as a cue that would be effectively separated from, or even antagonistic to, its known reverse signaling roles [27,30,35].…”