Intercellular molecular signaling regulates every aspect of development, from the very first cell fate decisions to communication between complex organ tissues. Much of what we know about molecular regulation of development in mammals comes from studies of mouse embryos. In mice, the first cell fate decision, which separates the outer, multipotent trophectoderm cells from the pluripotent inner cell mass, is regulated by the Hippo signaling pathway. It is known that silenced Hippo signaling in the outer cells maintains the cells’ polarity; however, my studies show that Hippo signaling does not direct the initiation of cell polarization in mouse embryos. The second cell fate decision in mouse embryos differentiates the inner cell mass into pluripotent epiblast and multipotent primitive endoderm. The Bone Morphogenic Protein (BMP) signaling pathway has been suggested to regulate preimplantation cell fate at this stage; however, I show that preimplantation lineage specification appears normal in mouse embryos that lack maternal and zygotic Smad4, an essential effector of canonical BMP signaling. Rather, my findings point to a previously unrecognized role for SMAD4 during early post-implantation stages, in which SMAD signaling restricts FGF signaling to promote epiblast growth and morphogenesis. In addition to these novel regulatory mechanisms in early cell fate, I present three technological advances in the study of early development, using recombinant fluorescent markers, more specific markers of pluripotency in reprogrammed stem cells, and ultra-low-input CUT&RUN to identify transcription factor binding sites in embryos. Altogether, these studies uncover novel mechanisms of cross-talk between regulatory pathways in development and present new strategies to investigate future questions in developmental biology.
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