Schwann cell mitosis in response to regenerating peripheral axons in vivo
ABSTRACT Schwann cell mitosis has been demonstrated in chronically denervated cat tibial nerves re-innervated by axons regenerating from the proximal stump of a coapted peroneal nerve. Thymidine incorporation rose above baseline levels at the axon front, with no detectable increase in more distal regions occupied by denervated Schwann cells. Schwann cells therefore enter S phase upon the arrival of a regenerating axon in vivo as previously described in tissue culture. Intraneural treatment of the denervated distal stump with Mitomycin C prior to re-innervation delayed the subsequent appearance of myelin formation. This supports the notion that axonally stimulated division of Schwann cells is a prerequisite for myelination during nerve regeneration. Axonal advancement was also retarded by drug treatment, possibly because of a reduced level of trophic support provided by the compromised Schwann cells. A comparable absence of myelin and poor re-innervation was found in chemically untreated distal stumps that had been maintained in the denervated state for prolonged periods when Schwann cell columns are known to undergo progressive atrophy. These observations suggest that nerve repair should be delayed for limited periods if efficacious regeneration is desired.
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ABSTRACT: Neuregulin 1 acts as an axonal signal that regulates multiple aspects of Schwann cell development including the survival and migration of Schwann cell precursors, the ensheathment of axons and subsequent elaboration of the myelin sheath. To examine the role of this factor in remyelination and repair following nerve injury, we ablated neuregulin 1 in the adult nervous system using a tamoxifen inducible Cre recombinase transgenic mouse system. The loss of neuregulin 1 impaired remyelination after nerve crush, but did not affect Schwann cell proliferation associated with Wallerian degeneration or axon regeneration or the clearance of myelin debris by macrophages. Myelination changes were most marked at 10 days after injury but still apparent at 2 months post-crush. Transcriptional analysis demonstrated reduced expression of myelin-related genes during nerve repair in animals lacking neuregulin 1. We also studied repair over a prolonged time course in a more severe injury model, sciatic nerve transection and reanastamosis. In the neuregulin 1 mutant mice, remyelination was again impaired 2 months after nerve transection and reanastamosis. However, by 3 months post-injury axons lacking neuregulin 1 were effectively remyelinated and virtually indistinguishable from control. Neuregulin 1 signalling is therefore an important factor in nerve repair regulating the rate of remyelination and functional recovery at early phases following injury. In contrast to development, however, the determination of myelination fate following nerve injury is not dependent on axonal neuregulin 1 expression. In the early phase following injury, axonal neuregulin 1 therefore promotes nerve repair, but at late stages other signalling pathways appear to compensate.Brain 07/2013; 136(Pt 7):2279-2297. DOI:10.1093/brain/awt148 · 10.23 Impact Factor
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ABSTRACT: Peripheral nerve injury is followed by a wave of Schwann cell proliferation in the distal nerve stumps. To resolve the role of Schwann cell proliferation during functional recovery of the injured nerves, we used a mouse model in which injury-induced Schwann cell mitotic response is ablated via targeted disruption of cyclin D1. In the absence of distal Schwann cell proliferation, axonal regeneration and myelination occur normally in the mutant mice and functional recovery of injured nerves is achieved. This is enabled by pre-existing Schwann cells in the distal stump that persist but do not divide. On the other hand, in the wild type littermates, newly generated Schwann cells of injured nerves are culled by apoptosis. As a result, distal Schwann cell numbers in wild type and cyclin D1 null mice converge to equivalence in regenerated nerves. Therefore, distal Schwann cell proliferation is not required for functional recovery of injured nerves.Molecular and Cellular Neuroscience 06/2008; 38(1):80-8. DOI:10.1016/j.mcn.2008.01.017 · 3.73 Impact Factor
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ABSTRACT: Hedgehog proteins are important in the development of the nervous system. As Desert hedgehog (Dhh) is involved in the development of peripheral nerves and is expressed in adult nerves, it may play a role in the maintenance of adult nerves and degeneration and regeneration after injury. We firstly investigated the Dhh-receptors, which are expressed in mouse adult nerves. The Dhh receptor patched(ptc)2 was detected in adult sciatic nerves using RT-PCR, however, ptc1 was undetectable under the same experimental condition. Using RT-PCR in purified cultures of mouse Schwann cells and fibroblasts, we found ptc2 mRNA in Schwann cells, and at much lower levels, in fibroblasts. By immunohistochemistry, Ptc2 protein was seen on unmyelinated nerve fibers. Then we induced crush injury to the sciatic nerves of wild-type (WT) and dhh-null mice and the distal stumps of injured nerves were analyzed morphologically at different time points and expression of dhh and related receptors was also measured by RT-PCR in WT mice. In dhh-null mice, degeneration of myelinated fibers was more severe than in WT mice. Furthermore, in regenerated nerves of dhh-null mice, minifascicular formation was even more extensive than in dhh-null intact nerves. Both dhh and ptc2 mRNA levels were down-regulated during the degenerative phase postinjury in WT mice, while levels rose again during the phase of nerve regeneration. These results suggest that the Dhh-Ptc2 signaling pathway may be involved in the maintenance of adult nerves and may be one of the factors that directly or indirectly determines the response of peripheral nerves to injury.Journal of Neurobiology 02/2006; 66(3):243-55. DOI:10.1002/neu.20216 · 3.84 Impact Factor