Abstract
SummarySlit-Robo signaling has been characterized as a repulsive signal for precise axon pathfinding and cell migration during embryonic development. Here, we describe a role for Sox2 in the regulation of Robo1 in Schwann cells and for Slit3-Robo1 signaling in controlling axon guidance within the newly formed nerve bridge following peripheral nerve transection injury. In particular, we show that macrophages form the outermost layer of the nerve bridge and secrete high levels of Slit3, while migratory Schwann cells and fibroblasts inside the nerve bridge express the Robo1 receptor. In line with this pattern of Slit3 and Robo1 expression, we observed multiple axon regeneration and cell migration defects in the nerve bridge of Sox2-, Slit3-, and Robo1-mutant mice. Our findings have revealed important functions for macrophages in the peripheral nervous system, utilizing Slit3-Robo1 signaling to control correct peripheral nerve bridge formation and precise axon targeting to the distal nerve stump following injury.
Highlights
Nerve transection injury following trauma often generates a nerve gap between the proximal and distal nerve stumps, which prevents correct re-targeting of regenerating axons into the distal nerve
Axon Pathfinding and Schwann Cell Migration Defects in Sox2 Knockout Mice Following Nerve Transection The Sox2 transcription factor is expressed by Schwann cells, is downregulated as they differentiate within the peripheral nervous system, but is upregulated following nerve injury (Le et al, 2005; Parrinello et al, 2010; Roberts et al, 2017)
Our data revealed that Sox2 is not required for myelin protein downregulation in Schwann cells after peripheral nerve injury that is in contrast to its negative regulatory role during developmental myelination and remyelination following injury in vivo (Roberts et al, 2017)
Summary
Nerve transection injury following trauma often generates a nerve gap between the proximal and distal nerve stumps, which prevents correct re-targeting of regenerating axons into the distal nerve. We study the effects of the loss of Sox in Schwann cells during peripheral nerve regeneration and show a dramatic regeneration defect of axonal pathfinding and Schwann cell migration in the sciatic nerve bridge of Sox knockout mice. We further relate this regeneration defect to Sox regulation of Robo expression in Schwann cells. A wider investigation of Slit and Robo expression in the mouse sciatic nerve bridge following injury shows that macrophages form the outermost layer of the nerve bridge and secrete high levels of Slit, while migrating Schwann cells and fibroblasts inside the nerve bridge express the Robo receptor.
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