BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
Cell and Developmental Biology Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.
Diabetes. 2017 Aug;66(8):2213-2219. doi: 10.2337/db16-1074. Epub 2017 May 11.
The high-mobility group box transcription factor SOX4 is the most highly expressed SOX family protein in pancreatic islets, and mutations in 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 is essential for the maintenance of β-cell number during the development of type 2 diabetes. Knockout of 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 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.
高迁移率族蛋白 SOX4 转录因子是胰岛中表达水平最高的 SOX 家族蛋白，而 基因突变与 2 型糖尿病发病风险增加相关。我们使用诱导型β细胞敲除小鼠模型来验证这样一个假说，即 SOX4 对于 2 型糖尿病发展过程中β细胞数量的维持是必需的。在 6 周龄时敲除 ，会导致葡萄糖耐量逐渐恶化，胰岛素分泌受损，并在 30 周龄时发展为糖尿病。免疫染色显示，敲除小鼠的β细胞数量减少，这是由于β细胞增殖减少了 39%。基因表达研究表明，细胞周期抑制剂 的诱导是导致敲除动物增殖减少的原因。总之，这项研究表明，SOX4 通过直接调节β细胞周期，对成年β细胞的复制是必需的。
