A midline switch of receptor processing regulates commissural axon guidance in vertebrates

TLDR

Commissural axon guidance requires complex modulation of growth cone sensitivity to midline cues, but the underlying mechanisms in vertebrates remain largely unknown. The study aims to uncover a molecular pathway that controls the gain of response to the midline repellent Semaphorin3B (Sema3B). The authors employed ex vivo and in vivo approaches to identify this pathway. The study demonstrates that Semaphorin3B/Plexin‑A1 signaling directs commissural axons, with calpain‑1–mediated processing of Plexin‑A1 silencing responsiveness before crossing, and suppression of calpain‑1 by floor‑plate cues (including NrCAM) enabling Plexin‑A1 accumulation and sensitization, revealing receptor‑processing modulation as a novel guidance mechanism.

Abstract

Commissural axon guidance requires complex modulations of growth cone sensitivity to midline-derived cues, but underlying mechanisms in vertebrates remain largely unknown. By using combinations of ex vivo and in vivo approaches, we uncovered a molecular pathway controlling the gain of response to a midline repellent, Semaphorin3B (Sema3B). First, we provide evidence that Semaphorin3B/Plexin-A1 signaling participates in the guidance of commissural projections at the vertebrate ventral midline. Second, we show that, at the precrossing stage, commissural neurons synthesize the Neuropilin-2 and Plexin-A1 Semaphorin3B receptor subunits, but Plexin-A1 expression is prevented by a calpain1-mediated processing, resulting in silencing commissural responsiveness. Third, we report that, during floor plate (FP) in-growth, calpain1 activity is suppressed by local signals, allowing Plexin-A1 accumulation in the growth cone and sensitization to Sema3B. Finally, we show that the FP cue NrCAM mediates the switch of Plexin-A1 processing underlying growth cone sensitization to Sema3B. This reveals pathway-dependent modulation of guidance receptor processing as a novel mechanism for regulating guidance decisions at intermediate targets.