E‐cadherin (CDH1) is involved in maintaining cell–cell adhesions in embryonic stem cells (ESCs). However, its function in the context of cell fate decisions is largely unknown. Using mouse ESCs (mESCs), we demonstrate that E‐cadherin and β‐catenin interact at the membrane and continue to do so upon internalization within the cell. Cdh1−/− mESCs failed to form tight colonies, with altered differentiation, marker expression and retention of pluripotency factors during differentiation. Interestingly, Cdh1−/− mESCs showed dramatically reduced β‐catenin levels. Transcriptional profiling of Cdh1−/− mESCs displayed a significant alteration in the expression of a subset of β‐catenin targets in a cell state‐ and GSK3β‐dependent manner. Our findings hint at hitherto unknown roles played by E‐cadherin in regulating the activity of β‐catenin in ESCs.

No abstract

E-CADHERIN is abundantly expressed in embryonic stem cells (ESCs) and plays an important role in the maintenance of cell-cell adhesions. However, the exact function of this molecule beyond cell adhesion, in the context of cell fate decisions is largely unknown. Using mouse ESCs (mESCs), we demonstrate that E-CADHERIN and β-CATENIN interact at the membrane and continue to do so upon internalization within the cell. Knockout of the gene encoding E-CADHERIN, Cdh1, in mESCs resulted in a failure to form tight colonies, accompanied by altered expression of differentiation markers, and retention of pluripotency factor expression during differentiation. Interestingly, Cdh1-/- mESCs showed a dramatic reduction in β-CATENIN levels. Transcriptional profiling of Cdh1-/- mESCs displayed a significant alteration in the expression of a subset of β-CATENIN targets, in a cell-state dependent manner. While treatment with a pharmacological inhibitor against GSK3β could rescue levels of β-CATENIN in Cdh1-/- mESCs, expression of downstream targets were altered in a context-dependent manner, indicating an additional layer of regulation within this subset. Together, our results reveal the existence of a cell-state-dependent regulation of β-CATENIN and its transcriptional targets in an E-CADHERIN dependent manner. Our findings hint at hitherto unknown roles played by E-CADHERIN in regulating the activity of β-CATENIN in ESCs.