Tead1 reciprocally regulates adult β-cell proliferation and function to maintain glucose homeostasis

Abstract

Diabetes ensues when there is a net decrease in functional β-cell mass. Efforts to increase β-cell mass are limited by a concurrent loss of mature function. The molecular mechanisms underlying the reciprocal regulation between β-cell proliferation and mature function are unclear. Here, we demonstrate that constitutive and inducible genetic deletion of Tead1 in mouse β-cells leads to diabetes. Tead1, the transcription factor downstream of the mammalianhippo pathway, has a developmental stage-specific critical function in β-cells and is required for maintenance of mature β-cell functional competence by direct transcriptional regulation of a network of critical β-cell transcription factors, including, Pdx1, Nkx6.1 and MafA. Concurrently, Tead1 directly activates Cdkn2a transcription in adult β-cells to inhibit proliferation. Studies in human β-cells demonstrate that Tead1 plays a similar regulatory role. Taken together, our findings uncover the non-redundant role of Tead1 in modulating the balance between proliferative capacity and functional competence.

Hippo Signaling Pathway in Pancreas Development

“…TEAD1 also activates the transcription of critical genes required for maintaining mature β cell function. These data indicate that TEAD1 controls, directly or indirectly, the gene regulatory network critical to maintain β cell functional competence and proliferative quiescence (Lee et al, 2020). Whether the function of TEAD1 in β cells is independent of Hippo pathway remains unknown.…”

“…Whether the function of TEAD1 in β cells is independent of Hippo pathway remains unknown. Several studies have shown that β cells do not express YAP; however, the expression of TAZ has been found in β cells (Lee et al, 2020). Thus, it will be interesting to find out if deletion of TAZ phenocopies deletion of TEAD1 in β cells.…”

“…In addition to TEAD1 regulating the proliferation of pancreatic progenitors, Lee et al studied TEAD1 function in β cells using two β cell specific Cre drivers, Rip Cre which results an early constitutive gene deletion from E15.5, and Mip CreER which deletes genes at the time of tamoxifen administration (Lee et al, 2020). The mice with TEAD1 deleted at E15.5 developed early diabetes at 5 weeks of age.…”

VGLL4 and MENIN function as TEAD1 corepressors to block pancreatic β cell proliferation

“…Although YAP expression cannot be detected in islets, 6 , 7 overexpression of YAP can increase β cell proliferation, 8 suggesting TEAD1 pathway is preserved and ready to be reactivated. Our previous data showed that TAZ expression could be detected in mouse islets, 5 but TAZ’s role in mature β cells remains unknown. Here, we demonstrate using in vivo β cell-specific deletion in mice that YAP and TAZ have no role in β cell function or proliferation.…”

“… 4 Our previous study showed that TEAD1 was preferentially expressed in adult mouse islets, whereas other members of the TEAD family are present at a 10-fold lower level (TEAD2) or not detected (TEAD3–4). 5 By far, YAP and TAZ are the most studied coactivators of TEAD. Although YAP expression cannot be detected in islets, 6 , 7 overexpression of YAP can increase β cell proliferation, 8 suggesting TEAD1 pathway is preserved and ready to be reactivated.…”