Ruff, C.A.D.B.; (2010) The role of growth associated transcription factors c-Jun and ATMIN in neuronal regeneration and repair. Doctoral thesis , UCL (University College London).

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Abstract

Subsequent to neuronal injury, increased levels of protein synthesis accompany associated rises in transcription factor expression. Two transcription factors involved in the cellular stress response are c-Jun and ATMIN. Neuron-specific deletion of c-Jun resulted in defects in perineuronal sprouting, lymphocyte recruitment and microglial activation. Motoneurons also exhibited an atrophic phenotype, reduced target reinnervation and resistance to cell death. Additionally, mutants lacking Jun expression in peripheral Schwann Cells exhibited decreased regeneration and target muscle reinnervation, with accompanying deficits in cell survival, which highlights the dual role of c-Jun in response to stress. Homozygous deletion of JNK1, JNK2 or JNK3, or substitution of the c-Jun N-terminal serine phosphoacceptor sites (ser63&73), with alanines (JunAA), did not produce a difference in response to injury. This evidence indicates that N-terminal phosphorylation of ser63&73 does not play an essential function for axonal regeneration in vivo, while the whole c-Jun is clearly needed to successfully mount a regenerative response. ATMINΔN mutants, which have CNS-specific Nestin::Cre-mediated ATMIN deletion, exhibited higher transcription factor expression (c-Jun, Activating Transcription Factor-3/ATF3) in facial motoneurons – both baseline and following peripheral facial axotomy - and increased central post-traumatic sprouting of CGRP-and galanin-immunoreactive motoneurites. Although there was no effect on gross functional recovery or neuronal cell death, retrograde transport of florescent markers (Fluoro-Gold, MiniRuby) revealed augmented branching under normal conditions and during the reinnervation of peripheral motor targets. In the spinal cord injury model, ATMINΔn animals showed increased numbers of corticospinal tract (CST) axons projecting to both dorsal horns and contralateral CST, as well as bilateral impairment in precise co-ordinated motor behaviour following dorsolateral hemisection. This highlights the role of ATMIN as an important regulator of axonal guidance and pruning in neuronal development and regeneration. Altogether, these findings demonstrate the essential roles of c-Jun and ATMIN in the neuronal stress response following nerve transection.

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