Abstract
E-cadherin-mediated cell-cell adhesion is critical for naive pluripotency of cultured mouse embryonic stem cells (mESCs). E-cadherin-depleted mESC fail to downregulate their pluripotency program and are unable to initiate lineage commitment. To further explore the roles of cell adhesion molecules during mESC differentiation, we focused on p120 catenin (p120ctn). Although one key function of p120ctn is to stabilize and regulate cadherin-mediated cell-cell adhesion, it has many additional functions, including regulation of transcription and Rho GTPase activity. Here, we investigated the role of mouse p120ctn in early embryogenesis, mESC pluripotency and early fate determination. In contrast to the E-cadherin-null phenotype, p120ctn-null mESCs remained pluripotent, but their in vitro differentiation was incomplete. In particular, they failed to form cystic embryoid bodies and showed defects in primitive endoderm formation. To pinpoint the underlying mechanism, we undertook a structure-function approach. Rescue of p120ctn-null mESCs with different p120ctn wild-type and mutant expression constructs revealed that the long N-terminal domain of p120ctn and its regulatory domain for RhoA were dispensable, whereas its armadillo domain and interaction with E-cadherin were crucial for primitive endoderm formation. We conclude that p120ctn is not only an adaptor and regulator of E-cadherin, but is also indispensable for proper lineage commitment.
Highlights
Pluripotent mouse embryonic stem cells can self-renew and differentiate into any given cell type within an organism
Recent advances in the field allow to obtain stem cells from virtually every patient. These stem cells could be instructed to form the desired cells that can be reintroduced to cure the patient. Before such therapies are suited for the clinic, we first need comprehensive knowledge of the molecular mechanisms that underlie cell fate decisions
We could unravel the exact molecular interaction that is required for p120ctn to drive the differentiation of stem cells towards primitive endoderm
Summary
Pluripotent mouse embryonic stem cells (mESCs) can self-renew and differentiate into any given cell type within an organism. They are isolated from the inner cell mass (ICM) of preimplantation blastocyst stage embryos and considered ‘naive’, with regard to their pluripotency status, whereas stem cells derived from the epiblast of the post-implantation embryo are considered ‘primed’ [1]. E-cadherin is a critical regulator of naive pluripotency [3], as its genetic inactivation in mESCs facilitates them to convert from a naive to a primed pluripotency state [4]. E-cadherin is required for proper compaction between the blastomeres of the morula stage embryo and for subsequent trophectoderm formation during the first cell fate segregation decision in embryos [5, 6]. As E-cadherin-null embryos do not form proper blastocysts, the role of E-cadherin during mouse embryogenesis beyond this stage remains elusive
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