Examination of Hnf6 and downstream effectors in postnatal endocrine function

Abstract

CELL AND DEVELOPMENTAL BIOLOGY

Examination of Hnf6 and downstream effectors in postnatal endocrine function

Kathryn D. Henley

Dissertation under the direction of Professor Maureen Gannon

The pancreas is an endodermally-derived organ responsible for the digestion of food and maintenance of glucose homeostasis. The endocrine pancreas is comprised of clusters of cells organized into islets of Langerhans, which are predominantly populated by the insulin-secreting beta cells. Absolute loss of beta cells or a decline in beta cell function compounded by decreased insulin sensitivity in the peripheral tissues results in Type I Diabetes or Type II Diabetes, respectively. Mouse models are frequently used to study the initiation, progression, and treatment of both Type I and Type II Diabetes. Hepatocyte nuclear factor 6 (Hnf6) is a transcription factor required for the development of the endocrine pancreas and necessary for expression of genes essential to endocrine function. The role of Sostdc1, a downstream effector of Hnf6 that antagonizes the BMP and Wnt pathways, was studied in the context of islet function after exposure to high fat diet (HFD); loss of Sostdc1 improved glucose homeostasis and insulin secretion in mice exposed to HFD. Additionally, the cooperative roles of Hnf6 and Pancretic and duodenal homeobox 1 (Pdx1) in postnatal islet function were examined. These studies revealed that during pancreatogenesis, Hnf6 and Pdx1 regulate genes required postnatally for islet function.