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

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.

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.