In Transected Nerves, Distal Repair Schwann Cells at the Injury Site 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 transected axons. After mechanical injury, distal Schwann cells adopted a repair phenotype characterized by changes in gene expression, elongation, and ability to guide axons across the injury site. In contrast, proximal Schwann cells associated with axons that regrew along aberrant paths at the injury site. In erbb2 mutants with greatly decreased Schwann cells, developmental axon growth was normal, but axonal regrowth after transection was greatly slowed and often misdirected. By examining animals with nerves partially populated by Schwann cells, we found that axons could regrow through regions devoid of Schwann cells, provided that at least one distal Schwann cell was at the injury site. Timelapse imaging revealed that distal Schwann cells contacted axons, which then regrew along the correct path. In irf8 mutants with greatly decreased macrophages, debris from transected axons was cleared on schedule, and axonal regrowth was normal. Our studies demonstrate that Schwann cells immediately distal to the injury site have a unique and essential role in axonal regrowth.