Geometric, cell cycle and maternal-to-zygotic transition-associated YAP dynamics during preimplantation embryo development

During the first cell fate decision in mammalian embryos the inner cell mass cells, which will give rise to the embryo proper and other extraembryonic tissues, segregate from the trophectoderm cells, the precursors of the placenta. Cell fate segregation proceeds in a gradual manner encompassing two rounds of cell division, as well as cell positional and morphological changes. While it is known that the activity of the Hippo signaling pathway and the subcellular localization of its downstream effector YAP dictate lineage specific gene expression, the response of YAP to these dynamic cellular changes remains incompletely understood. Here we address these questions by quantitative live imaging of endogenously tagged YAP while simultaneously monitoring geometric cellular features and cell cycle progression throughout cell fate segregation. We apply a probabilistic model to our dynamic data, providing a quantitative characterization of the mutual effects of YAP and cellular relative exposed area, which has previously been shown to correlate with subcellular YAP localization in fixed samples. Additionally, we study how nuclear YAP levels are influenced by other factors, such as the decreasing pool of maternally provided YAP that is partitioned to daughter cells through cleavage divisions, cell cycle-associated nuclear volume changes, and a delay after divisions in adjusting YAP levels to new cell positions. Interestingly, we find that establishing low nuclear YAP levels required for the inner cell mass fate is largely achieved by passive cell cycle-associated mechanisms. Moreover, contrary to expectations, we find that mechanical perturbations that result in cell shape changes do not influence YAP localization in the embryo. Together our work identifies how various inputs are integrated over a dynamic developmental time course to shape the levels of a key molecular determinant of the first cell fate choice.