After nerve injury, Schwann cells convert to a phenotype specialised to promote repair. But during the slow process of axonal regrowth, these repair Schwann cells gradually lose their regeneration-supportive features and eventually die. Although this is a key reason for the frequent regeneration failures in humans, the transcriptional mechanisms that control long-term survival and phenotype of repair cells have not been studied, and the molecular signalling underlying their decline is obscure. We show, in mice, that Schwann cell STAT3 has a dual role. It supports the long-term survival of repair Schwann cells and is required for the maintenance of repair Schwann cell properties. In contrast, STAT3 is less important for the initial generation of repair Schwann cells after injury. In repair Schwann cells, we find that Schwann cell STAT3 activation by Tyr705 phosphorylation is sustained during long-term denervation. STAT3 is required for maintaining autocrine Schwann cell survival signalling, and inactivation of Schwann cell STAT3 results in a striking loss of repair cells from chronically denervated distal stumps. STAT3 inactivation also results in abnormal morphology of repair cells and regeneration tracks, and failure to sustain expression of repair cell markers including Shh, GDNF and BDNF. Since Schwann cell development proceeds normally without STAT3, the function of this factor appears restricted to Schwann cells after injury. This identification of transcriptional mechanisms that support long-term survival and differentiation of repair cells will help identify, and eventually correct, the failures that lead to the deterioration of this important cell population.
Although injured peripheral nerves contain repair Schwann cells that provide signals and spatial clues for promoting regeneration, the clinical outcome after nerve damage is frequently poor. A key reason for this is during the slow growth of axons through the proximal parts of injured nerves repair Schwann cells gradually lose regeneration-supporting features and eventually die. Identification of signals that sustain repair cells is therefore an important goal. We have found that in mice the transcription factor STAT3 protects these cells from death and contributes to maintaining the molecular and morphological repair phenotype that promotes axonal regeneration. Defining the molecular mechanisms that maintain repair Schwann cells is an essential step towards developing therapeutic strategies that improve nerve regeneration and functional recovery.
Submitting author: Kristjan R. Jessen, Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom e-mail:
This work was funded by a Wellcome Trust Programme grant to KR Jessen and R Mirsky (074665), and MRC Project grant to KR Jessen and R Mirsky (G0600967), and grant agreement No. HEALTH-F2-2008-201535 from the European Community (FP7/2007-3013). C Benito was funded by the Marie Curie Research Grants Scheme, grant (271927).
The authors have no conflits of interest to declare
We thank Laura Feltri and Larry Wrabetz (State University of New York at Buffalo, Buffalo NY) for the gift of Mpz-Cre mice. We thank Ashwin Woodhoo (CIC bioGUNE, Bilbal, Spain) for dissection of E12 nerves for precursor cultures, and R Martini (University of Würzburg, Germany) for a gift of L1 antibodies.
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