Positional guidance for Schwann cells to build nerve bridge after injury requires Plexin-B1-mediated collision repulsion

Positional cues are critical to guide orientation of cell movement and morphological transformation during tissue morphogenesis. Positional guidance is particularly important in nerve repair after transection injury to build a new nerve bridge connecting the gap between the proximal and distal nerve stumps. However, the mechanisms governing longitudinal alignment of glial cells in the orientation of nerve axis remain unclear. Here, we reveal that in response to nerve injury, Schwann cells rely on guidance receptor Plexin B1 to orchestrate membrane/actin dynamics for morphological transformation and contact-based collision repulsion for spatial alignment during nerve repair, which requires contact with axons and regenerating growth cones. The Schwann cell alignment in turn provides positional guidance for the longitudinal alignment of macrophages and other stromal cells in the nerve bridge to safeguard axon pathfinding along the nerve axis. Collectively, our studies demonstrate the importance of axonal contacts and Plexin-B1 for providing positional guidance for Schwann cells to longitudinally align along the nerve axis to ensure correct orientation for axon regrowth during nerve regeneration. Overall design: To unveil the function of Plexin-B1 for Schwann Cell (SC) physiology after SNI, we derived primary SCs from Plxnb1-/- mice and WT littermate controls. Transcriptomes of SCs, in triplicate samples of WT and Plxnb1-/- SCs, were sequenced using bulk RNA-seq.