Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505114
Title: An investigation into the transcriptional control of the Schwann cell during differentiation, demyelization and disease
Author: Arthur-Farraj, Peter
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2008
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Abstract:
The generation of mature myelinating and non-myelinating Schwann cells from immature Schwann cells is regulated by signals from the axon. In the absence of axonal signals, for example during nerve injury, Schwann cells will return to an immature-like phenotype. However, Schwann cells retain the ability to re-differentiate after injury, demonstrating remarkable plasticity throughout adult life. Although these cellular transformations are normally beneficial, during diseases of the peripheral nervous system, they are often disrupted producing negative consequences. In this thesis, I have demonstrated a synergistic relationship between two signals, cyclic adenosine monophosphate (cyclic AMP) and p-neuregulin-1 (NRG1) in inducing myelin differentiation in cultured mouse Schwann cells. Furthermore, I found that the cyclic-AMP response element binding protein (CREB) family of transcription factors are required for this differentiation. Second, I have investigated the role of the transcription factor c-Jun in controlling Schwann cell responses after nerve injury. Using in vivo and in vitro approaches, I have found that c-Jun is an axonal-regulated injury factor that controls Schwann cell demyelination and dedifferentiation. Furthermore, Schwann cell derived c-Jun is crucial for adequate nerve regeneration and repair after injury. Finally, I investigated the functional properties of a mutant form of the my el in-related transcription factor Egr2 (Krox-20), which leads to severe congenital hypomyelinating neuropathy in humans. I found that mutant Egr2 is not transcriptionally inactive but retains residual wild-type Egr2 functions. More importantly, mutant Egr2 also demonstrates aberrant effects in Schwann cells, enhancing DNA synthesis, both in the presence and absence of the putative axonal mitogen, p-neuregulin 1. This is in stark contrast to wild-type Egr2, which causes withdrawal from the cell cycle.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.505114  DOI: Not available
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