Elucidating Mechanisms of Human Epiblast Development During Implantation

Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics

First Advisor

Sozen, Berna

Abstract

During human embryo implantation, the pluripotent epiblast undergoes a critical transition into an organized epithelium, requiring coordinated cell rearrangements to establish higher-order tissue organization. Despite its essential role in successful human development, the molecular mechanisms governing this process in a human-specific context remain poorly understood. In this dissertation, we integrate $\beta$-catenin transcriptional interactome analyses, comparative transcriptomics, and functional assays in human embryos, as well as in the first fully defined stem cell-based model of the human epiblast, to elucidate these mechanisms. We demonstrate that active WNT/$\beta$-catenin signaling, through TCF/LEF-mediated regulation, is essential for epithelial remodeling in the human epiblast, unlike its role in mouse embryos. Functional perturbations in human embryos and 3D human epiblast models reveal that WNT signaling directly modulates $\beta$-catenin-bound targets involved in lipid droplet synthesis and organization within the epiblast. Mechanistically, immunoprecipitation mass spectrometry identifies CYP2S1 as a $\beta$-catenin target that interacts with NME1, a key regulator linking lipid metabolism and epithelial integrity. Functional disruption of NME1 leads to loss of epithelialization, altered lipid droplet abundance and spatial organization, and altered junctional integrity, underscoring its crucial role in epiblast morphogenesis. Our findings uncover an unrecognized role of WNT-mediated lipid metabolism in shaping human epiblast architecture, revealing fundamental interspecies differences in early development between humans and mice at a clinically relevant stage of early pregnancy.

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