A conserved role of Hippo signaling in initiation of the first lineage specification event across mammals

Abstract

Our understanding of the molecular events driving cell specification in early mammalian development relies mainly on mouse studies, and it remains unclear whether these mechanisms are conserved across mammals, including humans. We have recently shown that the establishment of cell polarity via aPKC is a conserved event in the initiation of the trophectoderm (TE) placental program in mouse, cow, and human embryos. However, the molecular mechanisms transducing cell polarity into cell fate in cow and human embryos is unknown. Here, we have examined the evolutionary conservation of the molecular cascade downstream of aPKC in four different mammalian species: mouse, rat, cow, and human. Surprisingly, by morphokinetic and immunofluorescence analyses, we observe that rat embryos more closely recapitulate human and cow developmental dynamics, in comparison to the mouse. Nevertheless, in all four species, inhibition of the Hippo pathway by targeting LATS kinases is sufficient to drive ectopic TE initiation and downregulation of SOX2, a marker of the inner cell mass. Our comparative embryology approach uncovered intriguing differences as well as similarities in a fundamental developmental process among mammals, reinforcing the importance of cross-species investigations.

The Guinea Pig: A New Model for Human Preimplantation Development

“…1cii). Collectively, the expression patterns of these markers indicate that lineage specification does not commence in the compacted guinea pig embryo, aligning with observations in human, rat, and bovine 3 .…”

“…1bii). In contrast, CDX2 emerges in the human, bovine and rat embryo around the time of cavitation 3,21 . Here we see the progressive embryo maturation and distinct expression of CDX2+ emerging in outer cells during the 16C-32C stage, which corresponds to E4.5-E4.75 (Fig.…”

Lineage segregation in human pre-implantation embryos is specified by YAP1 and TEAD1

“…We confirmed our manual approach by measuring fluorescence intensities of YAP1 and GATA3 at the earlier stages when signals started to emerge, thus when weak signals are more prone to operator error (Fig. 4B) using the 3D Fiji/Image J Suite as previously described (Gerri et al , 2020, 2022).…”

Similarities and differences in placental development between humans and cynomolgus monkeys

“…Recent studies have shown that the deactivation of the Hippo signaling pathway is commonly observed in mouse, rat, cow, and human TE. 45,46 Mouse and human trophoblasts share similar epigenetic features. Specifically, tissue-dependent and differentially methylated regions between trophoblast and embryonic lineages are conserved between them.…”

“…Even though there might be species differences at the cellular level, knowledge from mouse experiments help understanding of placental formation in humans. Recent studies have shown that the deactivation of the Hippo signaling pathway is commonly observed in mouse, rat, cow, and human TE 45,46 . Mouse and human trophoblasts share similar epigenetic features.…”