Position-sensing established during compaction dictates cell fate in the mammalian embryo

Abstract

Precise patterning within the 3-dimensional context of tissues, organs and embryos implies that cells can sense their relative position. We still understand relatively little about how cells sense their relative position within small groups of cells. During preimplantation development, outside and inside cells rely on apicobasal polarity and the Hippo pathway to choose their fate. Despite recent findings suggesting that mechanosensing may be central to this process, the relationship between blastomere geometry (i.e. shape and position) and the Hippo pathway effector YAP remains unknown. To address this, we used a highly quantitative approach to collect and analyse information on the geometry and YAP localisation of individual blastomeres of mouse and human embryos. We find that the fraction of YAP in the nucleus responds to the proportion of exposed cell surface area rather than blastomere shape. To directly test the influence of blastomere position on YAP localisation we developed an approach using hydrogel based cylindrical cavities to alter blastomere arrangement in cultured embryos. Unbiased clustering analyses of blastomeres from such embryos reveal that the ability to respond to position emerges as early as the 8-cell stage during compaction and that altering the relative position of a blastomere within an embryo can alter its fate. Finally, we demonstrate that this response is lost upon inhibiting PKC signalling, linking it to the cell polarity. Our results pinpoint when during early embryogenesis cell specification decisions are initiated and show how blastomeres can sense their position in a polarity dependent manner to alter YAP localisation.3

Coordination between patterning and morphogenesis ensures robustness during mouse development

“…B 375: 20190562 inner population figure 2b(i) will push and flatten outer cells, thus stretching the apical domain and facilitating divisions parallel to the surface, which will counter the excess of inner cells (figure 2b). Broad apical domains are associated with lower contractility, an outside position and ultimately a TE fate [71,108,112,113], both in mouse and in human embryos [113]. On the other hand, an excess of outer cells will create competition for an outside position (figure 2b(ii)) to try and minimize surface energy.…”

“…Low contractility facilitates an outer position and a broad apical domain, which inhibits the Hippo pathway and promotes TE identity. Accordingly, mechanically forcing more cells into an outer position expands their apical surface and leads to an increase in YAP nuclear localization and CDX2 expression [113]. Conversely, cells with a narrow or no apical domain adopt an internal position and eventually an ICM fate [72,90,[94][95][96][111][112][113][114][115].…”

“…Accordingly, mechanically forcing more cells into an outer position expands their apical surface and leads to an increase in YAP nuclear localization and CDX2 expression [113]. Conversely, cells with a narrow or no apical domain adopt an internal position and eventually an ICM fate [72,90,[94][95][96][111][112][113][114][115]. The stabilization of a TE genetic programme causes commitment of most outer cells to a TE fate by the 32-cell stage [29,30,32,84].…”