VGLL4 and MENIN function as TEAD1 corepressors to block pancreatic β cell proliferation.
TEAD1 and the mammalian Hippo pathway regulate cellular proliferation and function, though their regulatory function in β cells remains poorly characterized. In this study, we demonstrate that while β cell-specific TEAD1 deletion results in a cell-autonomous increase of β cell proliferation, β cell-specific deletion of its canonical coactivators, YAP and TAZ, does not affect proliferation, suggesting the involvement of other cofactors. Using an improved split-GFP system and yeast two-hybrid platform, we identify VGLL4 and MENIN as TEAD1 corepressors in β cells. We show that VGLL4 and MENIN bind to TEAD1 and repress the expression of target genes, including FZD7 and CCN2, which leads to an inhibition of β cell proliferation. In conclusion, we demonstrate that TEAD1 plays a critical role in β cell proliferation and identify VGLL4 and MENIN as TEAD1 corepressors in β cells. We propose that these could be targeted to augment proliferation in β cells for reversing diabetes.