Abstract
Schwann cell reprogramming and differentiation are crucial prerequisites for neuronal regeneration and re-myelination to occur following injury to peripheral nerves. The neurotrophin receptor p75NTR has been identified as a positive modulator for Schwann cell myelination during development and implicated in promoting nerve regeneration after injury. However, most studies base this conclusion on results obtained from complete p75NTR knockout mouse models and cannot dissect the specific role of p75NTR expressed by Schwann cells. In this present study, a conditional knockout model selectively deleting p75NTR expression in Schwann cells was generated, where p75NTR expression is replaced with that of an mCherry reporter. Silencing of Schwann cell p75NTR expression was confirmed in the sciatic nerve in vivo and in vitro, without altering axonal expression of p75NTR. No difference in sciatic nerve myelination during development or following sciatic nerve crush injury was observed, as determined by quantification of both myelinated and unmyelinated nerve fiber densities, myelinated axonal diameter and myelin thickness. However, the absence of Schwann cell p75NTR reduced motor nerve conduction velocity after crush injury. Our data indicate that the absence of Schwann cell p75NTR expression in vivo is not critical for axonal regrowth or remyelination following sciatic nerve crush injury, but does play a key role in functional recovery. Overall, this represents the first step in redefining the role of p75NTR in the peripheral nervous system, suggesting that the Schwann cell-axon unit functions as a syncytium, with the previous published involvement of p75NTR in remyelination most likely depending on axonal/neuronal p75NTR and/or mutual glial-axonal interactions.
Highlights
Schwann cells are axon-ensheathing glial cells of the peripheral nervous system (PNS) and are essential in maintaining normal nerve function as well as facilitating nerve repair following injury
Upon introduction of Cre recombinase, the Ngfr genomic DNA flanked by loxP sites is inverted and expression of p75 neurotrophin receptor (p75NTR) in Schwann cells is replaced with that of mCherry, while Cre-negative (Cre−/−) littermate controls have unchanged p75NTR expression (Figure 1A)
Morphological and morphometrical analyses of SC-p75NTR-KO mice, we found that ablation of p75NTR in Schwann cells correlated with a reduced motor nerve conduction velocity but had no impact regarding remyelination or axonal growth after sciatic nerve crush injury. p75NTR is widely expressed in the nervous system during development and has even been considered as a neural crest marker (Wislet et al, 2018)
Summary
Schwann cells are axon-ensheathing glial cells of the peripheral nervous system (PNS) and are essential in maintaining normal nerve function as well as facilitating nerve repair following injury. Two subtypes of Schwann cells exist in the adult PNS, either myelinating or non-myelinating. Non-myelinating Schwann cells surround and segregate groups of several smalldiameter nociceptive axons, in a structure called Remak bundles. It is generally well accepted that binding of neurotrophins to the Trk receptors mediate survival and differentiation, but the specific functions of p75NTR in the PNS remains elusive. The controversy may partly be attributed to the fact that p75NTR is expressed by both neuronal and glial cell types and may have very different and even contradictory roles depending on cell type and temporal expression pattern, including survival signaling, cytoskeletal organization as well as the induction of cell death (Chao, 2003; Reichardt, 2006; Meeker and Williams, 2015), providing substantial cellular and molecular diversity of this receptor
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