Tead1 Reciprocally Regulates Adult β-Cell Proliferation and Function to Maintain Glucose Homeostasis

The low proliferative rate of adult β-cells presents a challenge for diabetes therapy to increase β-cell numbers while maintaining mature function. Although proliferative quiescence in β-cells is required to maintain functional competence, exemplified by glucose stimulated insulin secretion, the molecular underpinnings of this reciprocal relationship remain enigmatic. Here, we demonstrate that Tead1, the transcription effector of the mammalian-Hippo pathway drives developmental stage-specific β-cell proliferative capacity in conjunction with its functional maturation. Tead1 promotes adult β-cell mature identity by direct transcriptional control of a network of critical β-cell transcription factors, including, Pdx1, Nkx6.1 and MafA, while its regulation of Cdkn2a maintains proliferative quiescence. Consequently, mice with either constitutive or inducible genetic deletion of Tead1 in β-cells developed overt diabetes due to a severe loss of secretory function despite induction of proliferation. Furthermore, we show that Tead1 has a similar regulatory role in human β-cells. We propose that Tead1 is an essential intrinsic molecular switch coordinating adult β-cell proliferative quiescence with mature identity and functional competence to maintain glucose homeostasis.