β-cell mass is significantly reduced especially in the late stage of diabetes. Hence, increasing β-cell proliferation to increase β-cell mass remains a desirable goal for diabetes treatment. The mechanisms that regulate β cell proliferation and concurrent maintenance of mature function is not well understood. Hippo-TEAD pathways regulated proliferation in many tissues. Our data show that TEAD1 (Hippo) pathway activities were significantly reduced in mature β cell. TEAD1 knockout results in the cell-autonomous increase of β cell proliferation, while loss of TAZ has not change in β cell proliferation, suggesting that TEAD1 corepressors, rather than coactivators, play a dominant role in β-cells. Improved Split-GFP system and yeast two-hybrid platform were also adapted to screen TEAD1 cofactors in β cells. Our study showed that MENIN can bind to TEAD1 directly and the pocket area of TEAD1 is critical for this binding. VGLL4 and MENIN work as TEAD1 corepressors to inhibit the expression of target genes in β-cells, including FZD7 and CCN2, which leads to a restriction of β cell proliferation. We also found that TEAD1 can regulate TEAD1, and this auto-inhibition contributes to TEAD1 pathway inhibition with β cell maturity. Our study sheds light on the mechanisms involved in β cell maintenance of mature function and proliferation and offer the mechanistic basis for modulating TEAD pathway to increase proliferation in β cells.
F.Li: None. R.Liu: None. V.Negi: None. P.Yang: None. J.K.Lee: None. M.Moulik: None. V.Yechoor: n/a.