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Title: Distal transcriptional activators of the myelin basic protein gene in oligodendrocytes and Schwann cells
Author: Taveggia, Carla
ISNI:       0000 0001 3499 7812
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2002
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Myelin is a multilamellar sheath that wraps the axons in the Central Nervous System (CNS) and in the Peripheral Nervous System (PNS). It is required for normal development, axonal health and to facilitate impulse conduction. MBP, one of the major myelin proteins, is synthesised by both oligodendrocytes (OL) in CNS and Schwann cells (SC) in PNS. Its synthesis is regulated primarily at the transcriptional level. MBP transcription is activated as a part of a program of coordinate myelin gene expression during development, overlapping but specific in OL as compared to SC. The nuclear proteins that bind to the MBP promoter are largely unidentified. In vitro and in vivo studies show that activation of the MBP proximal promoter requires different DNA binding sites and proteins in OL as compared to SC. Recently, transgenic mice studies identified a SC enhancer (SCE) located 9.0Kb upstream of the transcriptional start site of MBP. In this work, we compared MBP transcription mechanisms in OL and SC. Transient transfection analyses, in primary cultures of OL and SC, confirm the importance of SCE, and suggest that SCE is an activator in both cell types, but it is an enhancer only in SC. Biochemical analyses show that there are regions differentially protected by SC and OL nuclear extracts that can account for differential function. Analysis of internal deletions and transversion mutations of SCE suggests that multiple cis-acting elements cooperate to produce activation. Analyses of stably transfected SC show that chromatin upregulates SCE activation at least three fold. Co-culture of these stably transfected SC and dorsal root ganglia neurons reveal that axons markedly activate SCE, by at least two orders of magnitude. These results describe a model in which to analyse SCE biochemistry and function and identify trans-acting signals from axons that regulate MBP transcription in SC.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral