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Pdx1 Maintains β Cell Identity and Function by Repressing an α Cell Program

2014; Cell Press; Volume: 19; Issue: 2 Linguagem: Inglês

10.1016/j.cmet.2013.12.002

1932-7420

Tao Gao, Brian D. McKenna, Changhong Li, Maximilian Reichert, James Nguyen, Tarjinder Singh, Chenghua Yang, Archana Pannikar, Nicolai M. Doliba, Tingting Zhang, Doris A. Stoffers, Helena Edlund, Franz Matschinsky, Roland Stein, Ben Z. Stanger,

Diabetes Management and Research

Pdx1 is a homeobox-containing transcription factor that plays a key role in pancreatic development and adult β cell function. In this study, we traced the fate of adult β cells after Pdx1 deletion. As expected, β-cell-specific removal of Pdx1 resulted in severe hyperglycemia within days. Surprisingly, a large fraction of Pdx1-deleted cells rapidly acquired ultrastructural and physiological features of α cells, indicating that a robust cellular reprogramming had occurred. Reprogrammed cells exhibited a global transcriptional shift that included derepression of the α cell transcription factor MafB, resulting in a transcriptional profile that closely resembled that of α cells. These findings indicate that Pdx1 acts as a master regulator of β cell fate by simultaneously activating genes essential for β cell identity and repressing those associated with α cell identity. We discuss the significance of these findings in the context of the emerging notion that loss of β cell identity contributes to the pathogenesis of type 2 diabetes.