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Regulation of target gene expression in sensory neurons by Brn3a


During the development of the vertebrate nervous system, cellular proliferation and differentiation result in the formation of a large number of specialized physical structures composed of many different types of cells. The phenotypic properties of a cell are largely controlled by the complement of proteins that the cell expresses. Thus, the formation of properly functioning neuronal circuitry requires precisely coordinated regulation of gene expression. Tissue-specific transcription factors play a critical role in the process of development by exerting spatiotemporal control over the expression of their specific target genes. Hundreds of transcription factors have been identified which exhibit tissue-specific expression in the nervous system. Many of these factors are critical for proper neural development, with their disruption leading to severe phenotypic abnormalities. Brn3a (Pou4f1) is a POU domain transcription factor with a highly specific and complex pattern of expression in the developing nervous system. Disruption of Brn3a function results in severe developmental abnormalities and neonatal lethality. We have identified programs of gene expression controlled by Brn3a in both the trigeminal ganglia (TG) and dorsal root ganglia (DRG) using microarray analysis of dissected tissue from wild-type and Brn3a null embryos in midgestation. These experiments indicate that Brn3a regulates similar, but distinct complements of transcripts in sensory ganglia at different axial levels. We then show, using in vivo chromatin immunoprecipitation (ChIP) assays, that Brn3a directly represses the expression of the neurogenic transcription factors NeuroD1 and NeuroD4 in the developing TG. Finally, we provide evidence that epigenetic modifications of chromatin play an integral role in determining the regulatory targets of Brn3a and contribute to target gene differences between the TG and DRG. The work presented in this dissertation has provided insight into the role of Brn3a in the developing sensory nervous system. It also demonstrates a clear role for chromatin modification in transcription factor target gene selection which may be relevant for many tissue-specific transcription factor

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