Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Catherine L. May

Abstract

Correct specification and maintenance of pancreatic islet cells is an intricate process. Previous studies have demonstrated the essential role transcription factors play in this process. For islet glucagon-producing alpha-cells one such transcription factor is the aristaless-related homeobox gene (Arx). Previous studies have demonstrated that Arx is necessary and sufficient for alpha-cell specification where ablation of Arx results in complete loss of the alpha-cell lineage and misexpression leads to conversion into an alpha-cell phenotype. However, the role of Arx in maintenance of alpha-cell fate as well the impact non-null mutations of Arx have on alpha-cell development has not been explored. In this dissertation, I utilize mouse models and pancreatic analysis to address this question. My results demonstrate that Arx is necessary to maintain alpha-cell fate during development as well as in the adult. Furthermore, analysis of a non-null expansion mutation of Arx suggests dual roles for this factor during alpha-cell specification in activation of alpha-cell fate and repression of non-alpha-cell fate. These findings expand the role of Arx in the islet alpha-cell as well as provide an attractive avenue for future therapies for type II diabetes.

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