REGULATION OF SCHWANN-CELL PROLIFERATION BY AXON TRANSPORT (WALLERIAN)

Abstract

Communication between axons and glia, although poorly understood, is vital for normal neural function. This work examines the effect of axotomy on distally-located Schwann cells in mammalian sciatic nerve. An hypothesis that fast anterograde axonal transport plays a role in initiating Schwann cell mitosis in Wallerian degeneration, is advanced and examined.;Initial studies attempted to determine a sensitive and specific marker of the Schwann cell response to axotomy. Synthesis of DNA, total RNA, and protein, as well as activity of ornithine decarboxylase, an enzyme associated with cell growth and repair, was measured at various times in distal stumps of transected mouse sciatic nerve. Levels of premitotic DNA synthesis, as measured by incorporation of {dollar}\sp 3{dollar}H-thymidine, were elevated earlier (by 1 day posttransection) and more specifically than the other markers. Unexpectedly, autoradiography revealed that {dollar}\sp 3{dollar}H-thymidine incorporation at 1 d posttransection was associated with endothelial rather than Schwann cells, the latter comprising the majority of proliferating cells by day 3 posttransection.;Subsequent studies of cat sciatic nerves traced the appearance and spread of mitotic activity along distal nerve stumps. After a lag of approximately 2.8 days posttransection, elevated incorporation of {dollar}\sp 3{dollar}H-thymidine was detectable proximally within nerve stumps from whence it spread anterogradely along distal stumps with an apparent rate of at least 200 mm/d.;These data suggested that fast anterograde axonal transport, which operates at 150-400 mm/d, might be a trigger of Schwann cell proliferation during Wallerian degeneration. This hypothesis was examined by studying the effects of 24-h cold block of axonal transport on Schwann cell proliferation in transected cat sciatic nerves. Results failed to support the hypothesis that Schwann cell proliferation is associated with entry into axons at the site of transection (or focal nerve injury) of substances which are transported distally to initiate mitosis. Further data suggested that the Schwann cell proliferative response can be triggered by progressive anterograde failure of fast anterograde transport after axotomy.;In summary, these studies characterize the spatio-temporal spread of mitotic activity anterogradely along degenerating mammalian sciatic nerve stumps, and support the hypothesis that initiation of some changes of Wallerian degeneration is associated with failure of fast anterograde axonal transport.