Sunday, May 11, 2025
5/11/2025
Signaling-regulated establishment of pluripotency in vivo - PROJECT SUMMARY The first priority of the mammalian embryo is to establish its own placenta, which will eventually be recognized and accepted by the mother. At the same time, the embryo must reserve fetal cells by endowing some with pluripotency. Decades of rigorous study have revealed the molecular mechanism that partly explains this first cell fate decision. Around the 16-cell stage, when the embryo is still a ball of cells, cells on the outer surface polarize and repress Hippo signaling. As a consequence of Hippo repression, transcription factors YAP and TAZ (WWTR1) enter the nuclei of the outer cells, where they partner with TEAD4 to promote expression of key regulators of placental (trophectoderm) fate. Excitingly, this mechanism, which we helped discover in mice, is conserved in humans, highlighting the utility of the mouse model as a discovery platform. Yet, a major mystery remained unsolved: how are the pluripotent cells specified? Are they pluripotent by virtue of being non- trophectoderm? Or is there a more active mechanism? Our lab discovered that the pluripotency factor SOX2 exhibits a unique expression pattern at the 16-cell stage. That is, when other pluripotency factors, such as OCT4 and NANOG are expressed in both inside and outside cells of the embryo, SOX2 is detected only in inside cells. This observation suggests that SOX2 helps actively specify the earliest stages of pluripotency. Through a series of experiments, we subsequently showed that SOX2 expression pattern is dependent on the YAP/TAZ/TEAD transcriptional complex, indicating that trophectoderm and pluripotency are regulated by Hippo signaling in parallel, starting at the 16-cell stage. We now seek to discover: 1) Does the SOX2 pattern provide the positional information to restrict the activity of other pluripotency factors to the inside cells of the embryo? 2) Do Sox2 paralogues work with SOX2 or other factors to promote the pluripotency of inside cells? 3) How do YAP/TAZ/TEAD mechanistically repress expression of Sox2 while promoting expression of trophectoderm genes in outer cells? Our team brings together expertise in high throughput genome editing, time-resolved analysis of single cell gene expression, and ultra-low input genomics, which are all needed to make the major mechanistic advances envisioned here. These studies will help reveal the generalizable principles of mammalian embryonic development that are fundamental to ensuring healthy pregnancy and child development.
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