Tbl1 promotes Wnt/β-catenin signaling-induced degradation of the Tcf7l1 protein in mouse ESCs.

Abstract

Activation of the Wnt/β-catenin signaling pathway by CHIR99021, a specific inhibitor of GSK3β, induces Tcf7l1 protein degradation, which facilitates the maintenance of an undifferentiated state in mouse embryonic stem cells (mESCs). However, the precise mechanism is still inconclusive. Here, we showed that the overexpression of transducin-β-like protein 1 (Tbl1) or its family member Tblr1 can decrease Tcf7l1 protein levels, while the knockdown of each increases Tcf7l1 levels without affecting Tcf7l1 transcription. Interestingly, only Tbl1, not Tblr1, interacts with Tcf7l1. Mechanistically, Tbl1 translocates from the cytoplasm into the nucleus in association with β-catenin after the addition of CHIR99021 and functions as an adaptor to promote the ubiquitination of the Tcf7l1 protein. Functional assays further revealed that enforced expression of Tbl1 is capable of delaying mESC differentiation. In contrast, the knockdown of Tbl1 attenuated the effect of CHIR99021 on Tcf7l1 protein stability and mESC self-renewal. Our results provide insight into the regulatory network of the Wnt/β-catenin signaling pathway in promoting the maintenance of naïve pluripotency.