SOX4 allows facultativeβ-cellproliferation through repression of cdkn1a

Abstract

The high-mobility group box transcription factor SOX4 is the most highly expressed SOX family protein in pancreatic islets, and mutations in Sox4 are associated with an increased risk of developing type 2 diabetes. We used an inducibleβ-cellknockout mouse model to test the hypothesis that Sox4 is essential for the maintenance ofβ-cellnumber during the development of type 2 diabetes. Knockout of Sox4 at 6 weeks of age resulted in timedependent worsening of glucose tolerance, impairment of insulin secretion, and diabetes by 30 weeks of age. Immunostaining revealed a decrease inβ-cellmass in knockout mice that was caused by a 39% reduction inβ-cellproliferation. Gene expression studies revealed that induction of the cell cycle inhibitor Cdkn1a was responsible for the decreased proliferation in the knockout animals. Altogether, this study demonstrates that SOX4 is necessary for adultβ-cellreplication through direct regulation of theβ-cellcycle.