Fazal, SV; (2017) Levels of Schwann cell c-Jun control nerve development and response to injury. Doctoral thesis , UCL (University College London).

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Abstract

Peripheral nerves have a remarkable ability to regenerate following nerve injury, unlike their counterparts in the central nervous system. This phenomenal ability of nerves to regenerate in the peripheral nervous system is due to cross communication between different cell populations, a focal group being the glial cells known as Schwann cells. The transcription factor c-Jun is highly expressed in distal stump Schwann cells following injury. It is this c-Jun expression in Schwann cells following peripheral nerve injury that is crucial for the cellular reprogramming of mature Schwann cells (Remak and Myelin Schwann cells) into repair Bungner Schwann cells. Repair Bungner Schwann cells are important for providing the necessary maintenance and trophic support to regenerating axons. Mice that lack c-Jun in their Schwann cells and therefore fail to express it after injury have impaired regeneration. With this idea in mind, it was of interest to see what happens when c-Jun is overexpressed in Schwann cells. Thus, a new transgenic mouse was bred to conditionally overexpress c-Jun in Schwann cells only. c-Jun protein levels were elevated 5 fold and 7 fold in heterozygous and homozygous mice respectively, in developing Schwann cells. The elevation of c-Jun specifically in Schwann cell nuclei in c-Jun overexpressing mice (heterozygous and homozygous), allowed in vivo examination of the effects of a graded increase in c-Jun expression on Schwann cells in uninjured and injured nerves. Evidence presented below suggests that Schwann cells can tolerate moderately elevated levels of c-Jun expression from birth (5 fold) without it being detrimental to nerve development. These observations demonstrate that heterozygous c-Jun overexpressing mice which show a substantial elevation in c-Jun protein level (which is localized to Schwann cell nuclei) compared to wildtype (WT), although there is an initial delay in myelination at postnatal day (P) 7, in adult life they achieve normal Schwann cell and nerve architecture, with the exception of modestly reduced myelin thickness. However in contrast to the heterozygotes, higher levels of c-Jun in Schwann cells from birth in homozygous mice results in severe myelin inhibition, which manifests itself very early on at P1. In the homozygous mice the strongly increased c-Jun expression in Schwann cells resulted in defects that included an obvious delay in myelination, thinner myelin sheaths (in those Schwann cells that eventually myelinated axons), increased Schwann cell proliferation and an increase in nerve area. These homozygous overexpressing mutant nerves were also examined for the presence of tumours or cellular arrangements that precede tumour formation, but no evidence was found to support this. To elucidate the potential significance of c-Jun elevation in Schwann cells after injury specifically in the proximal stump (where axons are still in contact with the neuronal cell body), the proximal stump of WT mice was compared with that of Schwann cells and axons in the proximal stump of a well-established Schwann cell c-Jun conditional knockout mouse (cKO). Proximal stump Schwann cell c-Jun was expressed very rapidly and the profile of Schwann cells was highly elevated as early as 1 hour following sciatic nerve transection, with this elevation being maintained up to 48 hours after nerve injury and further away from the injury site. The lack of Schwann cell c-Jun in the proximal stump did not affect the expression of some well known regeneration associated genes (RAGs), including c-Jun, ATF3, p-STAT3 Ser727 and Tyr705, yet had a modest effect on the elevation of GAP43, after injury in L4 DRG neurons. Schwann cell c-Jun in Schwann cells of the proximal stump has a small effect on axonal outgrowth following a conditioning lesion, shown in vivo. Neuronal cultures from L4 DRGs derived from WT and cKO mice (with sciatic nerve injuries), grown on myelin inhibitory substrate in vitro, suggest that Schwann cell c-Jun is not affecting neuronal outgrowth.

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