SOX4 Allows Facultative β-Cell Proliferation Through Repression of <i>Cdkn1a</i>

Abstract

The high-mobility group box transcription factor SOX4 is the most highly expressed SOX family protein in pancreatic islets, and mutations in <i>Sox4</i> are associated with an increased risk of developing type 2 diabetes. We used an inducible β-cell knockout mouse model to test the hypothesis that <i>Sox4</i> is essential for the maintenance of β-cell number during the development of type 2 diabetes. Knockout of <i>Sox4</i> at 6 weeks of age resulted in time-dependent worsening of glucose tolerance, impairment of insulin secretion, and diabetes by 30 weeks of age. Immunostaining revealed a decrease in β-cell mass in knockout mice that was caused by a 39% reduction in β-cell proliferation. Gene expression studies revealed that induction of the cell cycle inhibitor <i>Cdkn1a</i> was responsible for the decreased proliferation in the knockout animals. Altogether, this study demonstrates that SOX4 is necessary for adult β-cell replication through direct regulation of the β-cell cycle.