Sortilin Modulates Schwann Cell Signaling and Remak Bundle Regeneration Following Nerve Injury

Maj Ulrichsen; Nádia P Gonçalves; Simin Mohseni; Simone Hjæresen; Thomas L Lisle; Simon Molgaard; Niels K Madsen; Olav M Andersen; Åsa F Svenningsen; Simon Glerup; Anders Nykjær; Christian B Vægter

doi:10.3389/fncel.2022.856734

Sortilin Modulates Schwann Cell Signaling and Remak Bundle Regeneration Following Nerve Injury

Front Cell Neurosci. 2022 May 11:16:856734. doi: 10.3389/fncel.2022.856734. eCollection 2022.

Authors

Affiliations

¹ Danish Research Institute of Translational Neuroscience - DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
² Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
³ Neurobiological Research, Faculty of Health Sciences, Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
⁴ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁵ Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark.
⁶ Center of Excellence PROMEMO, Aarhus University, Aarhus, Denmark.

Abstract

Peripheral nerve regeneration relies on the ability of Schwann cells to support the regrowth of damaged axons. Schwann cells re-differentiate when reestablishing contact with the sprouting axons, with large fibers becoming remyelinated and small nociceptive fibers ensheathed and collected into Remak bundles. We have previously described how the receptor sortilin facilitates neurotrophin signaling in peripheral neurons via regulated trafficking of Trk receptors. This study aims to characterize the effects of sortilin deletion on nerve regeneration following sciatic crush injury. We found that Sort1 ^- ^/ ^- mice displayed functional motor recovery like that of WT mice, with no detectable differences in relation to nerve conduction velocities and morphological aspects of myelinated fibers. In contrast, we found abnormal ensheathment of regenerated C-fibers in injured Sort1 ^- ^/ ^- mice, demonstrating a role of sortilin for Remak bundle formation following injury. Further studies on Schwann cell signaling pathways showed a significant reduction of MAPK/ERK, RSK, and CREB phosphorylation in Sort1 ^- ^/ ^- Schwann cells after stimulation with neurotrophin-3 (NT-3), while Schwann cell migration and myelination remained unaffected. In conclusion, our results demonstrate that loss of sortilin blunts NT-3 signaling in Schwann cells which might contribute to the impaired Remak bundle regeneration after sciatic nerve injury.

Keywords: NT-3; Remak bundle; Schwann cell; TrkC; nerve injury; sortilin.