Impaired peripheral nerve regeneration in a mutant line of transgenic mice with a Schwann cell defect

Schwann cell-axon interactions in the development, maintenance, and regeneration of the normal peripheral nervous system are complex. A previously described transgene-induced insertional mutation (BPFD#36), now referred to as Enervated (Enr), results in disrupted Schwann cell-axon interactions. Peripheral nerve crush and transplant experiments were conducted to further characterize this disrupted cellular interaction. In this report, I demonstrate that injury to the peripheral nerve leads to impaired regeneration in Enr mice. Morphologic and morphometric analyses reveal an impairment in which mutant peripheral nerves do not achieve the regenerative efforts attained by nerves in wild type mice. Moreover, abnormal Schwann cell-axon interactions remain after injury, as evidenced by the relatively frequent ultrastructural finding of unmyelinated large diameter axons in the regenerating nerves of mutant mice. There are fewer myelinated fibers per mm{dollar}sp2{dollar} (p {dollar}<{dollar}.05) and thinner myelin sheaths (p {dollar}<{dollar}.05) around regenerating axons in the nerves of homozygous mutant mice compared to wild type mice at 28 days after crush injury to the sciatic nerve.; Additionally, nerve graft experiments indicate that the impairment in regeneration is due to a Schwann cell defect. Morphologic findings in conjunction with molecular analysis of regenerating nerves suggest that the Enr defect causes a disruption in the ability of 'early' Schwann cells to differentiate into a more mature phenotype. There is 11-fold less steady state levels of mRNA for glial fibrillary acidic protein (GFAP) in homozygous mutant regenerating nerves at seven days after crush injury compared to wild type mRNA levels of GFAP. This, in conjunction with the similar levels of mRNA for the low-affinity nerve growth factor receptor (NGFr) in both wild type and mutant mice at seven days after injury, suggests a defect in the ability of Schwann cells to differentiate after injury from an 'early' NGFr positive and GFAP negative Schwann cell phenotype to a 'bipotential' NGFr positive and GFAP positive Schwann cell phenotype. The Schwann cell differentiation defect could explain both the peripheral neuropathy and impaired peripheral nerve regeneration observed in Enr mice.