Gay, Robert Daniel; (1998) Neuronal gene regulation by Pou family transcription factors. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The Oct-2 and Brn-3 transcription factors show restricted spatial and temporal expression during neuronal development and in the adult organism. They are known to play important roles in regulating gene expression in neuronal cells. To date, however, only a small number of genes directly regulated by these factors have been identified and studied. Previous studies of the modular structure of the Oct-2 protein have identified three distinct repression domains. The mechanism of transcripitional repression employed by these three domains has not been investigated, although it has been proposed that each repressor domain interacts with components of the basal transcription complex. It was therefore proposed to investigate the mechanism of action of each of these three domains. An assay system was employed to study the ability of each domain to interfere with transcriptional activation by a range of different transcriptional activators. As a result of these studies it was found that each of the domains function by alternate mechanisms. These findings reveal Oct-2 to be a complex and precise regulator of gene expression, the characteristic of which are discussed. The most recently identified gene directly regulated by Oct-2 is the neuronal nitric oxide synthase (nNOS) gene. Studies of the promoter of the highly related inducible nitric oxide synthase (iNOS) gene have revealed the presence of an octamer DNA binding site. Since Oct-2 mediates transcriptional activation via the octamer site in other gene promoters it was proposed to determine whether the Oct-2 transcription factor regulates iNOS gene expression in a similar manner as seen for nNOS. The work presented in this thesis shows that both Oct-2 and the Brn3 transcription factors activate the iNOS gene promoter. As a result we proposed to investigate the mechanism of action and the relevance of the octamer sequence in the regulation of this gene. These studies have revealed that the octamer motif is essential for the activation of the iNOS gene by these transcription factors although depending upon cell type and thus cell specific factors the iNOS gene may be activated by Brn-3 in the absence of a functional octamer motif. The ability of these factors to interact with other transcription factors was also investigated. The results of these investigations is presented and discussed in this thesis.

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