The lh3 Glycosyltransferase Directs Target-Selective Peripheral Nerve Regeneration

Abstract

Summary Functional PNS regeneration requires injured axons to return to their original synaptic targets, yet the mechanisms underlying target-selective regeneration have remained elusive. Using live-cell imaging in zebrafish we find that regenerating motor axons exhibit a strong preference for their original muscle territory, and that axons probe both correct and incorrect trajectories extensively before selecting their original path. We show that this process requires the glycosyltransferase lh3 and that post-injury expression of lh3 in Schwann cells is sufficient to restore target-selective regeneration. Moreover, we demonstrate that Schwann cells neighboring the transection site express the lh3 substrate collagen4a5 and that during regeneration collagen4a5 destabilizes axons probing inappropriate trajectories to ensure target-selective regeneration, possibly through the axonal repellant slit1a. Our results demonstrate that selective ECM components match subpopulations of regenerating axons with their original targets, and reveal a previously unappreciated mechanism that conveys synaptic target selection to regenerating axons in vivo.

To reverse or not to reverse? A systematic review of autograft polarity on functional outcomes following peripheral nerve repair surgery

“…Their work suggests that Schwann cells neighboring a lesion site induce changes that guide axonal regeneration. Regenerating axons that probe inappropriate trajectories are destabilized, which ensures target‐selective regeneration (Isaacman‐Beck, Schneider, Franzini‐Armstrong, & Granato, ). This may explain why no clinical differences are seen between reversed and normal orientation groups, as the majority of axons may retain their target specificity.…”

Repair Schwann cell update: Adaptive reprogramming, EMT, and stemness in regenerating nerves

“…This is completely rescued through re‐expression of lh3 solely in Schwann cells. Interestingly ventral branch motorneurons regenerate normally suggesting that subsets of Schwann cells are responsible for target selective re‐innervation after nerve injury (Isaacman‐Beck et al, )…”

Axonal regeneration in zebrafish spinal cord

“…The role of Wnt in directing peripheral axon growth has not been studied in its entire gamut. But Schwann cells in specific regions express glycosyl transferase Ih3 resulting in collagen4a5 expression and thus repel axons towards inappropriate trajectories (Isaacman‐Beck et al., ). Several axonal attractants/repellants are upregulated in zebrafish SCI (Table ) (Hui et al., ).…”