In transected nerves, distal repair Schwann cells are required at the injury site to direct and accelerate axonal regrowth

Abstract

In vertebrate peripheral nerves, damaged axons can regrow after injury, but the outcomes of regeneration are variable and often incomplete. Schwann cells in injured nerves are important for repair, but their actions at different positions and stages of nerve repair are not well understood. We have investigated the roles of Schwann cells in a larval zebrafish nerve injury model, in which nerves are visible in living animals during development, the initial injury response, and regrowth of the transected axons. After mechanical injury, distal Schwann cells adopt a repair phenotype characterized by changes in marker expression, elongation, and ability to guide axons across the injury site. In contrast, proximal Schwann cells are not sufficient to guide axons across the injury site, and they associate with axons that regrow along aberrant paths. In erbb2 mutants lacking Schwann cells, developmental axon growth is normal, but after transection, axonal regrowth is greatly slowed and often misdirected. By examining animals with nerves partially populated by Schwann cells, we find that axons can regrow through regions devoid of Schwann cells, provided that at least one distal Schwann cell is at the injury site. Timelapse imaging reveals that distal Schwann cells extend processes toward the injury site, which contact and guide axons regrowing from the proximal nerve stump. In irf8 mutants lacking macrophages, debris from transected axons is cleared on schedule, and axonal regrowth is normal. Our studies demonstrate that Schwann cells immediately distal to the injury site have a unique and essential role in axonal regrowth. Main PointsO_LIAfter nerve transection in larval zebrafish, proximal and distal Schwann cells have distinct functions at injury site C_LIO_LIA single distal repair Schwann cell is sufficient for axonal regrowth C_LIO_LIAxonal regrowth is normal in mutants without macrophages C_LI