EphB signaling directs peripheral nerve regeneration through Sox2-dependent Schwann cell sorting.
The peripheral nervous system has astonishing regenerative capabilities in that cut nerves are able to reconnect and re-establish their function. Schwann cells are important players in this process, during which they dedifferentiate to a progenitor/stem cell and promote axonal regrowth. Here, we report that fibroblasts also play a key role. Upon nerve cut, ephrin-B/EphB2 signaling between fibroblasts and Schwann cells results in cell sorting, followed by directional collective cell migration of Schwann cells out of the nerve stumps to guide regrowing axons across the wound. Mechanistically, we find that cell-sorting downstream of EphB2 is mediated by the stemness factor Sox2 through N-cadherin relocalization to Schwann cell-cell contacts. In vivo, loss of EphB2 signaling impaired organized migration of Schwann cells, resulting in misdirected axonal regrowth. Our results identify a link between Ephs and Sox proteins, providing a mechanism by which progenitor cells can translate environmental cues to orchestrate the formation of new tissue.
Parrinello
Simona
S
MRC Laboratory for Molecular Cell Biology and the UCL Cancer Institute, University College London, Gower Street, London WC1E 6BT, UK.
Napoli
Ilaria
I
Ribeiro
Sara
S
Wingfield Digby
Patrick
P
Fedorova
Marina
M
Parkinson
David B
DB
Doddrell
Robin D S
RD
Nakayama
Masanori
M
Adams
Ralf H
RH
Lloyd
Alison C
AC
D000818:Animals; D001369:Axons / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology; D009416:Nerve Regeneration; D010525:Peripheral Nerves / Q000502:physiology*; D051381:Rats; D036183:Receptor, EphB2 / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D012583:Schwann Cells / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction
D015820:Cadherins; D055748:SOXB1 Transcription Factors; C527784:Sox2 protein, rat; D036183:Receptor, EphB2