Zhu M, Cornwall-Scoones J, Wang P, Handford CE, Na J, Thomson M, Zernicka-Goetz M.
During the early stages of the pregnancy, the cells of the mammalian embryos differentiate into trophectoderm (TE), the progenitors of the placenta; and inner cell mass (ICM), the clump of cells that will give rise to embryonic tissues and yolk sac. A key event that mediates the TE-ICM fate bifurcation is the establishment of an apical domain on each cell. The formation of the apical domain is programmed to take place at 2.5 days after fertilisation in the mouse embryo, and 3-4 days in the human embryo. This timing is inflexible and resistant to various experimental perturbations. However, the molecular basis that is responsible for apical domain formation, as well as the temporal regulation for this invariant developmental clock remains unclear.
Here, Zhu et al investigated these two questions and identified two conditions as the timing factors for apical domain formation specifically at the 8-cell stage in the mouse embryo. The first being the zygotic expression of two transcription factors Tfap2c and Tead4; and the second the activation of RhoA signalling. Importantly, premature induction of the expression of Tfap2c, Tead4 and RhoA signalling allows the advance in the timing of apical domain formation. To understand how these three factors establish the apical domain, the authors combined quantitative imaging and biophysical modelling approach and define that the expression of Tfap2c and Tead4 controls the cooperative recruitment of the apical proteins, whereas the level of RhoA controls lateral mobility of the apical proteins. The balanced force between cooperative recruitment and lateral mobility allows the emergence of the apical domain with proper shape. Overall, this work indicates a direct role of zygotic genome activation in regulating the timing of cell polarization. Beyond identifying the key molecules sufficient to establish cell polarization, we also provide a biophysical understanding of the mechanism by which these molecules act to build cell polarization in the mammalian embryo.
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