Journey of the mouse primitive endoderm: from specification to maturation

Abstract

The blastocyst is a conserved stage and distinct milestone in the development of the mammalian embryo. Blastocyst stage embryos comprise three cell lineages which arise through two sequential binary cell fate specification steps. In the first, extra-embryonic trophectoderm (TE) cells segregate from inner cell mass (ICM) cells. Subsequently, ICM cells acquire a pluripotent epiblast (Epi) or extra-embryonic primitive endoderm (PrE, also referred to as hypoblast) identity. In the mouse, nascent Epi and PrE cells emerge in a salt-and-pepper distribution in the early blastocyst and are subsequently sorted into adjacent tissue layers by the late blastocyst stage. Epi cells cluster at the interior of the ICM, while PrE cells are positioned on its surface interfacing the blastocyst cavity, where they display apicobasal polarity. As the embryo implants into the maternal uterus, cells at the periphery of the PrE epithelium, at the intersection with the TE, break away and migrate along the TE as they mature into parietal endoderm (ParE). PrE cells remaining in association with the Epi mature into visceral endoderm. In this review, we discuss our current understanding of the PrE from its specification to its maturation. This article is part of the theme issue ‘Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom’.

Human naïve stem cell models reveal the role of FGF in hypoblast specification in the human embryo

“…Moreover, NANOG/GATA6 double positive cells had low-mid expression of NANOG. These observations are consistent with previous descriptions of a mutually antagonistic interaction between these transcription factors in the mouse ICM 23,24 . Few cells cultured in PXGL co-express NANOG/GATA6 with no PDGFRA expression detected (Figure 2D).…”

Self-organization of embryonic stem cells into a reproducible embryo model through epigenome editing

“…To analyze potential signaling pathway ligand-receptor interactions between clusters of different cell types, we used CellChat [57,58] to analyze paired expression of ligand-receptors between different clusters in CPEMs. We found predicted activity of pathways known to regulate early embryogenesis in specific ways, such as the Fgf pathway, Pdgf pathway and Bmp pathway [59][60][61][62][63][64] (Figure 5C, Supplementary Figure 12D-E [35,49]. Supporting this predicted interaction, we observe a higher ratio of ParE in CPEMs grown from mixed cells (30% ParE-like) compared to sgGata6-induced cells only, which do not receive TS-cell signals (15% ParE-like) (Supplementary Figure 12F).…”

“…CRISPRa can be used to directly and efficiently activate regulatory elements of cell fate-determining transcription factors to induce robust and homogeneous lineage differentiation in stem cells. We generated a doxycycline-inducible CRISPRa embryonic stem cell line to activate endogenous regulatory elements of two major cell fate-determining transcription factors, Cdx2 (sgCdx2-mESCs) and Gata6 (sgGata6-mESCs), that are expressed in TS cells and PrE cells respectively [10,[31][32][33][34][35].…”

A geometrical model of cell fate specification in the mouse blastocyst

“…The Epiblast becomes the embryo proper with the PrE making supporting tissue. The FGF signaling pathway is known to regulate the second of these two transitions though the exact mechanism through which it acts is still under debate [5, 6]. Two receptors respond to the FGF ligand, FGFR1 is present in all ICM cells, and FGFR2 in PrE only, but both contribute to the lineage decision and partially compensate [7,8].…”