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2025-12
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Biomedical Sciences
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Each year, more than three million infants are born in the United States (US). However, approximately ten percent of women experience infertility or miscarriage, and around three percent of newborns are affected by congenital disabilities. Despite decades of research, the genetic underpinnings of developmental disorders are still unknown, largely due to the limited understanding of the mechanisms that govern the complexity of human embryonic development. Gastrulation is a fundamental stage of human development in which pluripotent or epiblast-like cells differentiate into the three germinal layers: ectoderm, mesoderm, or endoderm, which give rise to all tissues and organs of the body. This process also establishes the body axes, laying the foundation for the embryo’s spatial organization. Gastrulation requires precise spatial and temporal regulation of key signaling pathways, including BMP, WNT, NODAL, and FGF signaling, which guide cell fate decisions, germ layer formation, and body axis patterning. While these pathways have been studied extensively, the mechanisms regulating their activity remain incompletely understood. Our lab has identified the Hippo signaling pathway as a critical regulator of gastrulation. The transcriptional effector YAP1 primarily mediates the activity of the Hippo signaling pathway. Although YAP1 is well known for its roles in cell proliferation and organ size control, particularly in the contexts of cancer and tissue regeneration, its precise functions during early embryogenesis remain poorly defined despite being essential for proper development.
Here, we uncover a novel role for YAP1 in the epiblast during gastrulation, where it regulates essential developmental signaling pathways and is required for establishing the anteroposterior axis. To shed light on the role of YAP1 in gastrulation, we establish a novel methodology to examine gene expression profiles in mouse embryos using single-cell RNA sequencing. Using a conditional Yap1 knockout in the mouse epiblast (Sox2-Cre), we show that loss of Yap1 disrupts the expression of key developmental genes, including Nodal, Wnt3, and Fgf8, and enhances differentiation toward primitive streak lineages. Mechanistically, we performed a proximity labeling assay in human embryonic stem cells (hESCs) and found that YAP1 interacts with the chromatin-associated protein QSER1 to regulate lineage-specific gene expression. YAP1 recruits QSER1 to restrict RNA Polymerase II access at lineage gene loci, thereby repressing premature transcription. In human 2D gastruloids, QSER1 depletion phenocopies YAP1 loss, leading to increased NODAL expression and hyperactivation of the pathway. Moreover, YAP1 is required for proper anterior-posterior axis formation in the human 3D gastruloid model. Inhibition of YAP1 enhances axial elongation and accelerates differentiation of hESCs toward the cardiac lineage. Additionally, deletion of Yap1 during late gastrulation impairs cardiac development. We find that YAP1 is essential for atrial lineage specficiation through retinoic acid signaling in cardiac progenitor cells. Together with mouse and hESC models, this work defines a previously unrecognized role of YAP1 in controlling cell fate decisions during gastrulation.
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