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Role of the two functional domains of the Brn-3a transcription factor in neuronal survival and differentiation

Reference	BB/D521314/1
Principal Investigator / Supervisor	Professor David Latchman
Co-Investigators / Co-Supervisors	Professor Andrew Copp
Institution	University College London
Department	Institute of Child Health
Funding type	Research
Value (£)	207,351
Status	Completed
Type	Research Grant
Start date	23/02/2006
End date	22/08/2009
Duration	42 months

Abstract

Brn-3a, a POU family transcription factor, plays a key role in the development of the nervous system by promoting neuronal differentiation and exerting an anti-apoptotic effect. By constructing two strains of knock out mice, we have shown that these two functions require distinct domains of Brn-3a. Thus, the POU domain is sufficient for promoting neuronal differentiation whilst an additional N-terminal domain is required for the anti-apoptotic effect. In this project, we will analyse in detail the developmental defects in these novel mouse strains in terms of neuronal survival and axonal outgrowth. The effects observed will be related to the expression patterns of the long and short forms of Brn-3a (respectively containing or lacking the N-terminal domain) and of molecules involved in cell survival and axonal outgrowth. These experiments will shed light on the role of two distinct domains of Brn-3a in mediating its key functions in development and the mechanisms by which these domains achieve their effects.

Summary

The Brn-3a regulatory protein plays a key role in the development of the nervous system and its absence is incompatible with survival. Brn-3a exerts its effects in two ways, firstly by enhancing the differentiation of cells to a mature neuronal phenotype and secondly, by enhancing neuronal survival. We have demonstrated that two distinct regions of the Brn-3a molecule are responsible for these two different effects. In this project we will analyse in detail the manner in which these two regions produce respectively, enhanced neuronal differentiation and neuronal survival. This work will enhance our understanding of the normal development of the nervous system and the manner in which it is regulated by Brn-3a, as well as the potential use of Brn-3a as a means of promoting enhanced neuronal survival in neurodegenerative diseases.

Committee	Closed Committee - Genes & Developmental Biology (GDB)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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