Sox9 regulates alternative splicing and pancreatic beta cell function [human]
Type 2 Diabetes Mellitus (T2D), a multifactorial disease, can result from perturbations in numerous pancreatic genes. We describe a previously unanticipated role for Sox9, a transcriptional regulator of embryonic pancreas and endocrine cell development, in mature beta cells. Our data demonstrate that Sox9 has continued function in beta cells as they mature, and elimination of Sox9 compromises beta cell activities. Sox9-depleted rodent beta cells fail to appropriately secrete insulin and exhibit glucose intolerance in aging animals, mimicking the progressive degeneration observed in T2D. Human beta cells lacking SOX9 are functionally impaired with stunted first phase insulin secretion. In both rodent and human, Sox9 loss in beta cells disrupts alternative splicing patterns, with significant implications for maintenance of cellular function. Thus, our data uncover a novel, unprecedented role for a developmental transcription factor in mature beta cell function. Overall design: To investigate SOX9 function in human adult pancreatic beta cells, TALEN technology was used to generate a Mel1-INS-GFP inducible SOX9 knockout reporter line. The line was differentiated to mature beta cells and treated with doxycycline to silence SOX9 expression.