Abstract
During mammalian development, the challenge for the embryo is to override intrinsic cellular plasticity to drive cells to distinct fates. Here, we unveil novel roles for the HIPPO signaling pathway in controlling cell positioning and expression of Sox2, the first marker of pluripotency in the mouse early embryo. We show that maternal and zygotic YAP1 and WWTR1 repress Sox2 while promoting expression of the trophectoderm gene Cdx2 in parallel. Yet, Sox2 is more sensitive than Cdx2 to Yap1/Wwtr1 dosage, leading cells to a state of conflicted cell fate when YAP1/WWTR1 activity is moderate. Remarkably, HIPPO signaling activity resolves conflicted cell fate by repositioning cells to the interior of the embryo, independent of its role in regulating Sox2 expression. Rather, HIPPO antagonizes apical localization of Par complex components PARD6B and aPKC. Thus, negative feedback between HIPPO and Par complex components ensure robust lineage segregation.
Highlights
During embryogenesis cells gradually differentiate, adopting distinct gene expression profiles and fates
We previously showed that Sox2 is restricted to inside cells by a Cdx2-independent mechanism (Wicklow et al, 2014), which differs from Oct4 and Nanog, which are restricted to the inner cell mass by CDX2 (Niwa et al, 2005; Strumpf et al, 2005)
To identify the mechanisms regulating Sox2 expression during blastocyst formation, we focused on how Sox2 expression is normally repressed in the trophectoderm to achieve inside cell-specific expression
Summary
During embryogenesis cells gradually differentiate, adopting distinct gene expression profiles and fates. Progenitors of inner cell mass are first morphologically apparent at the 16 cell stage as unpolarized cells residing inside the morula (reviewed in Frum and Ralston, 2017). At this stage, pluripotency genes such as Pou5f1 (Oct4) and Nanog, do not label inside cells (Dietrich and Hiiragi, 2007; Niwa et al, 2005; Palmieri et al, 1994; Strumpf et al, 2005). The exclusive study of Cdx regulation does not provide direct knowledge of how pluripotency is established because the absence
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