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An investigation into the transcriptional control of the Schwann cell during differentiation, demyelination and disease

Arthur-Farraj, P.; (2008) An investigation into the transcriptional control of the Schwann cell during differentiation, demyelination and disease. Doctoral thesis, UCL (University College London).

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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. Firstly, in this thesis, I have demonstrated a synergistic relationship between two signals, cyclic adenosine monophosphate (cyclic-AMP) and \beta-neuregulin-1 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. Secondly, 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, expressed in Schwann cells, is an axonal-regulated injury factor that controls. demyelination and dedifferentiation. Furthermore, Schwann cell derived c-Jun is crucial for functional nerve regeneration and repair after injury. Finally, I investigated the functional properties of a mutant form of the-transcription factor, Egr2 (Krox-20). Wild-type Egr2 is required for Schwann cell myelination whereas mutant Egr2 (S382R, D383Y) leads to severe congenital hypomyelinating neuropathy in humans. I found that mutant Egr2 is-not transcriptionally inactive but retains residual wild-type Egr2 functions, when expressed in cultured rat Schwann cells. More importantly, this mutant Egr2 has aberrant effects in Schwann cells, enhancing DNA synthesis both in the presence and absence of the putative axonal mitogen, \beta-neuregulin 1. This is in stark contrast to wild-type Egr2, which causes withdrawal from the cell cycle.

Type:Thesis (Doctoral)
Title:An investigation into the transcriptional control of the Schwann cell during differentiation, demyelination and disease
Language:English
Additional information:Authorisation for digitisation not received. The abstract contains LaTex text. Please see thesis for rendered equations
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Cell and Developmental Biology

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