Begbie, Joanne Louise; (1996) The differential expression and activity of the Brn3 family of POU domain transcription factors. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Bm-3a, Bm-3b and Bm-3c, are closely related members of the Bm-3 sub-family of POU domain transcription factors. The expression of this family has been examined in the developing and adult sensory ganglia by non-isotopic in situ hybridization. These studies show that Bm-3a expression can be seen in the majority of neurons in the dorsal root ganglia (DRG) and trigeminal ganglion throughout development, while expression of Bm-3b is not detected until post-natal stages. Furthermore, the apparent expression of Bm-3a in the mouse at embryonic day 9.5 (E9.5), suggests that it precedes expression of Bm-3b and Bm-3c. As observed for Bm-3a, the expression of Bm-3c can be seen in the majority of cells in the DRG and trigeminal ganglion at E12.5, although at lower levels. However, a progressive restriction of the expression of Bm-3c to a subset of neurons is observed during development. In the adult DRG, Bm-3c expression can be seen in 20% of neurons, corresponding mainly to neurons of intermediate diameter and showing no correlation to any one particular marker of previously identified neuronal populations. The expression of the Bm-3 family in the adult DRG shows no significant response to peripheral nerve section. In contrast, Oct-2, a member of the POU II subclass, was shown to be up-regulated, suggesting a potential role in the response of sensory neurons to peripheral damage. Studies of the reciprocal effects of Bm-3a and Bm-3b by domain interchange between the proteins have previously shown that although the POU domain can activate artificial promoters, activation of the internexin gene promoter requires the N-terminal region of Bm-3a. Results presented in this report of experiments using different domains of the proteins fused to the GAL4 DNA-binding domain, show that the N-terminal region can act as an independent activation domain, although distance and position of the binding site relative to the transcriptional start point appear to affect this ability. In contrast, the POU domain of each factor is unable to modulate transcription unless in contact with DNA, suggesting that DNA binding may induce a conformational change allowing interaction with other factors which are required for transcriptional activation.

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