The role of c-Jun and Notch signalling in Schwann cell development and peripheral nerve regeneration.
Doctoral thesis, UCL (University College London).
Unlike their counterparts in the CNS, nerves in the PNS are able to regenerate following injury. One of the key factors facilitating this is the plasticity of the glial cells, the Schwann cells. Following nerve injury Schwann cells demyelinate and dedifferentiate back to a phenotype related to that seen in the perinatal nerve as part of a process termed Wallerian degeneration. This enables them to provide trophic support to the neurons and a permissive surface for regrowing axons. Notch signalling and the transcription factor c-Jun have been implicated in driving some aspects of this process (Parkinson et al., 2008; Woodhoo et al., 2009). In this study I show that c-Jun plays an essential role in controlling the Schwann cell response to nerve injury. In its absence there is a marked reduction in the axonal regeneration rate. There is also a persistent failure of motor neurons to reinnervate target muscles and no recovery of motor and sensory function. In contrast to the role of c-Jun I show that Notch signalling is inhibitory to successful nerve repair. Axonal outgrowth, remyelination, reinnervation of targets and functional recovery are all accelerated in its absence. I go on to reveal that one of the mechanisms underlying this regeneration failure is likely to be a direct suppression of genes known to be beneficial to regeneration possibly as a result of reduced c-Jun levels. In addition to its role in regeneration, Notch signalling plays a fundamental part in the development of the Schwann cell (Woodhoo et al., 2009). In order to further explore this finding I investigated the role of the Notch negative regulator Numb. Numb is an endocytic protein that controls cell polarity and functions in axon growth and synapse formation. I find that Numb is expressed throughout the Schwann cell lineage with the highest levels present at the onset of myelination. Using retroviruses to either overexpress or reduce Numb levels with shRNAs I show that Numb blocks the transition from the Schwann cell precursor to immature Schwann cell phenotype in vitro. Numb may also play a role in Schwann cell myelination, as it acts independently or in concert with Krox20 and cyclic AMP to induce myelin gene expression. After nerve injury Numb expression is increased in the nerve suggesting a possible role for Numb in Schwann cell remyelination.
|Title:||The role of c-Jun and Notch signalling in Schwann cell development and peripheral nerve regeneration|
|Additional information:||Permission for digitisation not received|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Cell and Developmental Biology|
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