Elizabeth Tweedie's Research
REGULATION AND FUNCTION OF HNF6 IN PANCREATIC ENDOCRINE DEVELOPMENT
My project involved understanding the role of Hepatic nuclear factor 6(Hnf6), a transcription factor whose expression is necessary for proper pancreas development. Hnf6 is widely expressed during pancreatic development, but is absent from adult endocrine cells. My studies better defined the timepoints and cell types in which Hnf6 is expressed during pancreas development. Additionally, I determined the effects of loss of Hnf6 specifically from pancreatic endocrine progenitor cells.Furthermore, I found that downregulation of Hnf6 late in gestation is imperative for normal b cell development and function. Transgenic mice that misexpress Hnf6 in adult endocrine cells (pdx1PBHnf6) have impaired glucose- and secretagogue-stimulated insulin secretion, and have a severe downregulation of MafA, a major regulator of insulin transcription. Importantly, b cells in these mice appear unable to achieve terminal differentiation, and thus, do not function properly. My findings support a model in which Hnf6 is necessary for commitment of cells to the endocrine lineage (via activation of neurogenin3), but must be down-regulated in order to permit terminal differentiation of b cells.