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The roles of SOX4 and MED15 in the development and maintenance of pancreatic β-cells

University of British Columbia

Pancreatic beta-cells (β-cells) are essential for the maintenance of blood glucose homeostasis, as the primary insulin-secreting cells of the body. During embryogenesis, β-cells differentiate from pancreatic progenitor cells, and following birth, these cells re-enter the cell-cycle and proliferate to maintain a sufficient adult population of β-cells. Transcription factors (TFs) such as neurogenin3 (Neurog3) are essential for endocrine cell specification within the pancreas, while other TFs are required in adult β-cells to maintain their function. Despite the identification of many TFs throughout β-cell development, how TFs regulate the transition between cell states, and how these TFs engage the RNA Polymerase II holoenzyme to regulate transcription is unknown. To address these questions, this thesis examines the role of Sry-related HMG-box 4 (SOX4) and Mediator 15 (MED15) in β-cell development and the adult β-cell state. Work in this thesis has established that in mice, SOX4 is expressed in pancreatic progenitor cells and cooperates with NEUROG3 to activate Neurog3 expression. This demonstrated a requirement for SOX4 in endocrine progenitor cell specification. SOX4 continued to be expressed in endocrine specified cells, and was essential for Neurod1 and Pax4 induction, TFs required for β-cell specification. High-fat diet (HFD)-fed mice with inducible SOX4 deletion in β-cells also exhibited glucose intolerance, due to decreased β-cell mass and replication rate. Loss of Sox4 led to the upregulation of the cell-cycle inhibitor Cdkn1a, a gene that prevents G1-S cell-cycle transition. Additionally, Med15 deletion in pancreatic progenitors demonstrated reduced NEUROG3 expression, and reduced endocrine cell numbers. MED15 deletion following endocrine specification also led to reduced β-cell numbers. Finally, Ins1-Cre facilitated deletion of MED15 in β-cells revealed that its function varied depending on cell-state, with compromised β-cell function if expression is lost during β-cell maturation. These data are the first to determine when SOX4 is required for pancreatic endocrine specification in mice and which targets are directly regulated by SOX4. In addition, the first known in-vivo role for MED15 in mammals is identified, demonstrating that it is an indispensable factor for β-cell differentiation and function. Collectively, these findings contribute to the understanding of how TFs regulate β-cell states.

Text

2017-12-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/60212

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/