and the Rose F. Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, Bronx, NY 10461 U.S.A.
Brain Research (Impact Factor: 2.84). 09/1985; 341(1):16-25. DOI: 10.1016/0006-8993(85)91467-2
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.
"Nerve injury and repair is associated with two phases of Schwann cell proliferation: the first phase is due to loss of axonal contact and peaks around 3 days post-injury (Bradley and Asbury, 1970; Stoll et al., 1989; Carroll et al., 1997; Stoll and Muller, 1999; Griffin and Thompson, 2008). The second phase of proliferation occurs as axons enter the denervated nerve stump (Pellegrino and Spencer, 1985). Because of the role of NRG1 in Schwann cell proliferation during development (Dong et al., 1995; Parkinson et al., 2004; Perlin et al., 2011) and in the post-natal period (Chen et al., 2003), we investigated the role of NRG1 in modulating Schwann cell proliferation following injury. "
[Show abstract][Hide abstract] 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.
"a Note that the total numbers of studies for each experimental nerve injury are not necessarily the sum of individual measures because more than one measure was frequently used in the studies. tion (Pellegrino and Spencer, 1985; Birchmeier and Nave, 2008). "
[Show abstract][Hide abstract] ABSTRACT: Animal models of nerve compression, crush, and transection injuries of peripheral nerves have been subject to extensive study in order to understand the mechanisms of injury and axon regeneration and to investigate methods to promote axon regeneration and improve functional outcomes following nerve injury. Six outcome measures of regenerative success including axon and neuron counts, muscle and motor unit contractile forces, and behavior are reviewed in the context of nerve injury types, crush, transection and nerve repair by direct coaptation, or transection and repair via a nerve graft or conduit. The measures are evaluated for sciatic, tibial, common peroneal, femoral, single nerve branches such as the soleus nerve, and facial nerves. Their validity is discussed in the context of study objectives and the nerve branch. The case is made that outcome measures of axon counts and muscle contractile forces may be valid during the early phases of axon regeneration when regenerating sprouts emerge asynchronously from the proximal nerve stump and regenerate towards their denervated targets. However, care must be taken especially when experimental interventions differentially affect how many neurons regenerate axons and the number of axons per neuron that sprout from the proximal nerve stumps. Examples of erroneous conclusions are given to illustrate the need for researchers to ensure that the appropriate outcome measures are used in the evaluation of the success of peripheral nerve regeneration.
Annals of anatomy = Anatomischer Anzeiger: official organ of the Anatomische Gesellschaft 05/2011; 193(4):321-33. DOI:10.1016/j.aanat.2011.04.008 · 1.48 Impact Factor
"We did not find such defects in regenerating cyclin D1 −/− nerve. In a similar study, (Pellegrino and Spencer 1985) have shown that pre-treatment of denervated distal nerve with mitomycin C prior to re-innervation delays regeneration and remyelination, suggesting that Schwann cell proliferation plays an important role in promoting remyelination and regeneration of the injured PNS. The discrepancy between our result and these earlier studies might be explained by a possible cytotoxic effect of mitomycin C on regenerating axons or on the associated Schwann cells that would affect remyelination and regeneration. "
[Show abstract][Hide abstract] 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.
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