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Author's School

Graduate School of Arts and Sciences

Author's Department/Program

Division of Biology and Biomedical Sciences (Developmental Biology)

Advisor(s)

Kristen L. Kroll, Kyunghee Choi, David I. Gottlieb, James E. Huettner, Jason C. Mills, James B. Skeath

Language

English (en)

Date of Award

8-15-2008

Degree Type

Restricted Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Abstract

Roles of neurogenin and geminin in vertebrate neurogenesis

Proneural basic helix-loop-helix transcription factors regulate cell fate commitment and differentiation in neurogenesis. However, their proneural functions are not well understood, in part due to a lack of information about their target genes. Here, we identified direct transcriptional targets of the bHLH transcription factor Neurogenin. We found that Neurogenin regulates neurogenesis by activating transcription factors, cell signaling components, and genes regulating cytoskeleton rearrangement and cell migration. Some of these target genes are induced by Neurogenin in both Xenopus and mouse, and comprise conserved effectors mediating Neurogenin activity in vertebrates. We computationally defined consensus sequences for Neurogenin binding and identified responsive enhancers regulated by Neurogenin in seven target loci. These enhancers commonly contained clustered, conserved consensus binding sites and drove neural tissue-specific expression in transgenic Xenopus embryos. We used the Neurogenin binding consensus and a computational approach to predict additional target genes involved in neural development at a genome-wide level. Taken together, these data demonstrated that Neurogenin preferentially recognizes neurogenesis-related targets through an enhancer signature of clustered consensus binding sites and regulates neurogenesis by activating a core set of transcription factors that form a robust transcriptional network. Previously, we also demonstrated that the novel nuclear protein Geminin maintains neural progenitors and blocks neuronal differentiation, at least in part by antagonizing Neurogenin's ability to activate its target genes. To define how Geminin regulates neurogenesis, we recently identified a subset of Neurogenin direct targets that are repressed by Geminin. We are now using these target genes to characterize how antagonism between Geminin and Neurogenin regulates transcriptional programs controlling neurogenesis.

DOI

https://doi.org/10.7936/K7TQ60X9

Comments

Permanent URL: https://doi.org/10.7936/K7TQ60X9

Print version available in library catalog at http://catalog.wustl.edu:80/record=b3807155~S2.

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