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Published May 24, 2024 | in press
Journal Article Open

Tead4 and Tfap2c generate bipotency and a bistable switch in totipotent embryos to promote robust lineage diversification

Zhu, Meng ORCID icon
Meglicki, Maciej ORCID icon
Lamba, Adiyant ORCID icon
Wang, Peizhe ORCID icon
Royer, Christophe ORCID icon
Turner, Karen
Jauhar, Muhammad Abdullah ORCID icon
Jones, Celine
Child, Tim ORCID icon
Coward, Kevin ORCID icon
Na, Jie ORCID icon
Zernicka-Goetz, Magdalena1 ORCID icon
  • 1. ROR icon California Institute of Technology

Abstract

The mouse and human embryo gradually loses totipotency before diversifying into the inner cell mass (ICM, future organism) and trophectoderm (TE, future placenta). The transcription factors TFAP2C and TEAD4 with activated RHOA accelerate embryo polarization. Here we show that these factors also accelerate the loss of totipotency. TFAP2C and TEAD4 paradoxically promote and inhibit Hippo signaling before lineage diversification: they drive expression of multiple Hippo regulators while also promoting apical domain formation, which inactivates Hippo. Each factor activates TE specifiers in bipotent cells, while TFAP2C also activates specifiers of the ICM fate. Asymmetric segregation of the apical domain reconciles the opposing regulation of Hippo signaling into Hippo OFF and the TE fate, or Hippo ON and the ICM fate. We propose that the bistable switch established by TFAP2C and TEAD4 is exploited to trigger robust lineage diversification in the developing embryo.

Copyright and License

This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024. 

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Acknowledgement

We thank all reviewers and A. Andersen from the Life Science Foundation for their constructive comments and extremely valuable suggestions. We thank S. Malas (The Cyprus Institute) for providing the Gata3–GFP transgenic line, C. Graham for helping to process human embryos for immunostaining in University of Oxford and S. Junyent Espinosa, W. Hu and Z. Liao for the help in some pilot experiments at Caltech. This work was supported by grants from the Wellcome Trust (098287/Z/12/Z), European Research Council (ERC) (669198), Leverhulme Trust (RPG-2018-085), Open Philanthropy/Silicon Valley, Weston Havens Foundations and National Institutes of Health R01HD100456A to M.Z.-G. Program of China grants 2017YFA0102802 and 2019YFA0110001 to J.N. M.Z. is a Human Frontier Science program long-term fellow. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Contributions

M.Z. and M.Z.-G. conceived the project. M.Z., M.M., A.L., P.W., C.R. and M.A.J. performed the experiments. M.Z. and P.W. analyzed the data. K.T., C.J., T.C. and K.C. provided the human embryo samples. M.Z.-G. and J.N. supervised the project.

Data Availability

The bulk RNA-sequencing data of Tfap2c and Tead4 RNAi at the eight-cell stage mouse embryo were deposited as previously described28 (GSE124755). All other raw data for making the graphs in the paper, as well as the raw images used in figures can be found in the Source data and Supplementary information sections in the manuscript. Source data are provided with this paper.

Extended Data Fig. 1 Expression of Tfap2c, Tead4 and activated Rho GTPase are sufficient to advance the first cell fate decision.

Extended Data Fig. 2 AMOT protein is tethered to the prematurely formed apical domain by the expression of Tfap2c, Tead4, and activated Rho GTPase.

Extended Data Fig. 3 Expression of Tfap2c, Tead4 and activated Rho GTPase promotes nuclear localisation of YAP in polar cells.

Extended Data Fig. 4 Tfap2c and Tead4 regulates the expression of Cdx2 before polarisation.

Extended Data Fig. 5 Expression profile of the GFP signal in GATA3-GFP transgenic mouse line.

Extended Data Fig. 6 Tfap2c and Tead4 activate the expression of TE and ICM cell fate regulators and Hippo components independent of Klf5.

Extended Data Fig. 7 Accessible TFAP2C binding sites are conserved between mouse and human genomic locus.

Source images for Figs. 1–6 and source images for Extended Data Figs. 1–6.

Source data Fig. 1

Source data Fig. 2

Source data Fig. 3

Source data Fig. 4

Source data Fig. 5

Source data Fig. 6

Source data Extended Data Fig. 1/Table 1

Source data Extended Data Fig. 4/Table 4

Source data Extended Data Fig. 6/Table 6

Conflict of Interest

The authors declare no competing interests.

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Additional details

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Created:
May 28, 2024
Modified:
May 28, 2024