The Role of Arx in Specification and Maintenance of Pancreatic Islet α-Cells

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.