Abstract
SummaryMammalian development begins with segregation of the extra-embryonic trophectoderm from the embryonic lineage in the blastocyst. While cell polarity and adhesion play key roles, the decisive cue driving this lineage segregation remains elusive. Here, to study symmetry breaking, we use a reduced system in which isolated blastomeres recapitulate the first lineage segregation. We find that in the 8-cell stage embryo, the apical domain recruits a spindle pole to ensure its differential distribution upon division. Daughter cells that inherit the apical domain adopt trophectoderm fate. However, the fate of apolar daughter cells depends on whether their position within the embryo facilitates apical domain formation by Cdh1-independent cell contact. Finally, we develop methods for transplanting apical domains and show that acquisition of this domain is not only required but also sufficient for the first lineage segregation. Thus, we provide mechanistic understanding that reconciles previous models for symmetry breaking in mouse development.
Highlights
Unlike many other model organisms, mammalian eggs lack polarity (Hiiragi and Solter, 2004; Motosugi et al, 2006; Rossant and Tam, 2004)
The apico-basal cell polarity observed in the 8-cell stage blastomeres and the orientation of their subsequent division have been proposed to play key roles in segregating inner cell mass (ICM) and TE fates (Johnson and Ziomek, 1981; Johnson, 2009)
The majority of the blastomeres aligned the mitotic spindle to the apico-basal axis (Figures 1C and 1D; 80% within 0–45, n = 20 of 25 cells) and underwent asymmetric division where the apical domain was differentially distributed between the daughter cells (86%, n = 19 of 22 cells with the ratio of Ezrin segregation higher than 3:1, marked with a dotted line in Figures 1D and 1E)
Summary
Unlike many other model organisms, mammalian eggs lack polarity (Hiiragi and Solter, 2004; Motosugi et al, 2006; Rossant and Tam, 2004). Subcellular localization of Yap is known to distinguish TE and ICM fates (Nishioka et al, 2009): nuclear Yap in outside cells upregulates the expression of Cdx, a transcription factor essential for TE-fate maturation (Ralston and Rossant, 2008; Strumpf et al, 2005), whereas in inside cells Yap is phosphorylated by Lats and remains cytoplasmic While both cell adhesion (Nishioka et al, 2009) and polarity (Hirate et al, 2013) have been proposed to control the differential localization of Yap, the decisive cue determining Yap localization remains elusive. The interplay between these two parameters (Cockburn et al, 2013; Hirate et al, 2013), combined with non-stereotypic lineage tree (Dietrich et al, 2015; Morris et al, 2010; Strnad et al, 2016; Watanabe et al, 2014) and stochastic cellto-cell variability in gene expression (Dietrich and Hiiragi, 2007; Plusa et al, 2008; Ralston and Rossant, 2008), has far hindered the identification of the symmetry-breaking cue that segregates the first lineages in mouse development (Wennekamp et al, 2013)
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