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We have previously demonstrated that differentiation of embryonic stem (ES) cells is associated with downregulation of cell surface E‐cadherin. In this study, we assessed the function of E‐cadherin in mouse ES cell pluripotency and differentiation. We show that inhibition of E‐cadherin‐mediated cell–cell contact in ES cells using gene knockout (Ecad −/− ), RNA interference (EcadRNAi), or a  trans homodimerization‐inhibiting peptide (CHAVC) results in cellular proliferation and maintenance of an undifferentiated phenotype in fetal bovine serum‐supplemented medium in the absence of leukemia inhibitory factor (LIF). Re‐expression of E‐cadherin in Ecad −/− , EcadRNAi, and CHAVC‐treated ES cells restores cellular dependence to LIF supplementation. Although reversal of the LIF‐independent phenotype in Ecad −/−  ES cells is dependent on the β‐catenin binding domain of E‐cadherin, we show that β‐catenin null (βcat −/− ) ES cells also remain undifferentiated in the absence of LIF. This suggests that LIF‐independent self‐renewal of Ecad −/−  ES cells is unlikely to be via β‐catenin signaling. Exposure of Ecad −/− , EcadRNAi, and CHAVC‐treated ES cells to the activin receptor‐like kinase inhibitor SB431542 led to differentiation of the cells, which could be prevented by re‐expression of E‐cadherin. To confirm the role of transforming growth factor β family signaling in the self‐renewal of Ecad −/−  ES cells, we show that these cells maintain an undifferentiated phenotype when cultured in serum‐free medium supplemented with Activin A and Nodal, with fibroblast growth factor 2 required for cellular proliferation. We conclude that  trans homodimerization of E‐cadherin protein is required for LIF‐dependent ES cell self‐renewal and that multiple self‐renewal signaling networks subsist in ES cells, with activity dependent upon the cellular context. STEM CELLS 2009;27:2069–2080

Abrogation of E‐Cadherin‐Mediated Cell–Cell Contact in Mouse Embryonic Stem Cells Results in Reversible LIF‐Independent Self‐Renewal