Regulation and Function of PTF1a in the Developing Nervous System




Meredith, David Miles

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Basic helix-loop-helix transcription factors serve many roles in development, including regulation of neurogenesis. Many of these factors are activated in naive neural progenitors and function to promote neuronal differentiation and cell-type specification. Ptf1a is a basic helix-loop-helix protein that is required for proper inhibitory neuron formation in several regions of the developing nervous system, including the spinal cord, cerebellum, retina, and hypothalamus. In addition, Ptf1a is essential for proper pancreas formation and exocrine function. In both the nervous system and pancreas, Ptf1a functions as a switch in cell fate determination. In the absence of Ptf1a, inhibitory neurons are lost and those cells instead adopt an excitatory identity. Similarly, endodermal progenitors will assume duodenal characteristics in place of a pancreatic identity when Ptf1a is lost. Like most other tissue-specific basic-helix-loop-helix factors, Ptf1a dimerizes with E-proteins and binds a degenerate hexameric E-box motif (CANNTG). Ptf1a is unique, however, in that it also requires the presence of Rbpj(l) to form an active transcription complex, PTF1. This interaction is central to Ptf1a function, as disruption of Ptf1a?s ability to bind Rbpj in vivo phenocopies the Ptf1a null in the nervous system and pancreas. Similarly, all targets described thus far for Ptf1a require an intact PTF1 binding site, which includes both an E-box and Rbpj binding site. In order to understand how a factor such as Ptf1a is capable of giving rise to such disparate organs, I wanted to place it in context of a larger regulatory network that directs a multipotent progenitor into a mature inhibitory neuron. Thus, I examine two regulatory schemes controlling Ptf1a expression during development in Chapters two and three. I then investigate direct Ptf1a targets in a genome-wide fashion using massively parallel sequencing technology in Chapters four and five. These efforts uncovered that Ptf1a employs several mechanisms to achieve proper cell-type specification, including initiation of transcription factor cascades, direct activation of inhibitory neuron machinery, and direct suppression of the excitatory neuron program. Furthermore, I identify novel binding modes and potential co-regulatory factors that could impart tissue-specific function.

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