Title: Maintenance of Beta Cell Identity and Function
Description: The acquisition of beta cell identity and function is a multistage process that involves the sequential regulation of specific factors and signals. The maintenance of beta cell identity and function is a process of comparable importance that requires persistent and continuous regulation. Loss of beta cell identity and/or reprogramming represents an important feature of beta cell dysfunction in genetic models of diabetes, as well as in patients with type 1 and type 2 diabetes. The factors and mechanisms involved in the acquisition and maintenance of beta cell identity are still not well understood. Nevertheless, several beta cell developmental transcription factors have been found to be important in the maintenance of its functional identity during the postnatal stage. Nkx2.2 is a transcription factor that is critical for the development and differentiation of beta cells both in mice and humans. In adults, Nkx2.2 is expressed in the entire beta cell population. However, due to the perinatal lethality of the Nkx2.2 null mice, the study of its function in adult beta cells has remained elusive.

For my dissertation work, I explored the function and mechanism of action of Nkx2.2 in the adult beta cell. I deleted Nkx2.2 specifically in beta cells during their maturation and in adults. Deletion of Nkx2.2 in beta cells caused rapid onset of diabetes due to the loss of insulin and the down-regulation of many beta cell functional genes. Concomitantly, Nkx2.2-deficient beta cells acquired non-beta cell endocrine features, resulting in populations of completely reprogrammed cells and bi-hormonal cells that have hybrid endocrine cell morphological characteristics. Molecular analysis in mouse and human islets revealed that Nkx2.2 is a conserved master regulatory protein that controls the acquisition and maintenance of a functional monohormonal beta cell identity by directly activating critical beta cell genes, and actively repressing genes that specify the alternative islet endocrine cell lineages. This study demonstrates the highly volatile nature of the beta cell; it is necessary to actively maintain expression of genes involved in beta cell function, but to also maintain repression of closely related endocrine gene programs.

These findings have potential applications that include the optimization of iPS cell differentiation protocols that aim to differentiate functional beta cells that remain safely locked into that identity state; as well as in future therapies that attempt to restore beta cells into a functional state.