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The timing mechanism for the first lineage specification in the mouse embryo

ABSTRACT: The transition from totipotency to pluripotency and subsequent differentiation in the mammalian embryo segregates embryonic and extra-embryonic progenitor cells. Despite its central importance, it remains entirely unknown how the timing of this major process is regulated. Here, we uncover that Tfap2c and Tead4 mediated transcriptional activity work in concert with the Rho GTPase mediated activation of actomyosin at the 8-cell stage as the upstream factors that trigger cell polarization and hence the first cell fate segregation in the mouse embryo. We show that they act together to control the establishment of cell polarisation, the activation of polarity dependent Hippo signalling, and the early expression of transcription factors required for the differentiation of the first extra-embryonic lineage. These results define the key step in the transition from totipotency to pluripotency and its relationship to the first cell fate specification event in the mouse embryo.

ORGANISM(S): Mus musculus

PROVIDER: GSE124755 | GEO | 2019/12/30

REPOSITORIES: GEO

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Project description:Mouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) exhibit a pluripotent developmental potential, contributing to all embryonic cell types, though rarely to extra-embryonic lineages. Unexpectedly, rare, totipotent-like stem cells have been identified in cultured ESC populations, suggesting the existence of a discrete molecular pathway that regulates the transition between totipotency and pluripotency in vitro. Here, we identify a single miRNA, miR-34a, whose deficiency in mouse pluripotent stem cells expands cell fate potential, giving rise to both embryonic and extra-embryonic lineages in vitro and in vivo. The expression profiles of the totipotent-like miR-34a-knockout murine pluripotent stem cells are characterized by a strong induction of MERVL endogenous retroviruses, a key molecular hallmark shared with totipotent mouse 2-cell blastomeres and totipotent-like mouse ESCs. In all three cell types, a subset of MERVL elements promotes the expression of specific isoforms of the proximal protein-coding genes. We demonstrate that miR-34a represses MERVL expression through transcriptional regulation, at least in part, by directly targeting the transcription factor GATA-binding protein 2 (Gata2). Since MERVL activation correlated precisely with the totipotent-like state, we hypothesized that the miR-34a/Gata2 pathway that regulates MERVL expression in ESCs/iPSCs also regulates the acquisition of totipotency in culture. Consistent with this hypothesis, gata2 knock-down in miR-34a-knockout mouse pluripotent stem cells not only reduced MERVL expression, but also abolished the expanded cell fate potential of these cells both in vitro and in vivo. Taken together, our findings not only provide key insights into the functional importance of miR-34a in restricting the totipotent cell fate potential of pluripotent stem cells, but also elucidate the underlying molecular basis by which miR-34a regulates the developmental potentials of ESCs/iPSCs.

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The timing mechanism for the first lineage specification in the mouse embryo

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