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Human embryo polarization requires PLC signaling to mediate trophectoderm specification

Zhu, Meng and Shahbazi, Marta and Martin, Angel and Zhang, Chuanxin and Sozen, Berna and Borsos, Mate and Mandelbaum, Rachel S. and Paulson, Richard J. and Molè, Matteo A. and Esbert, Marga and Titus, Shiny and Scott, Richard T. and Campbell, Alison and Fishel, Simon and Gradinaru, Viviana and Zhao, Han and Wu, Keliang and Chen, Zi-Jiang and Seli, Emre and de los Santos, Maria J. and Zernicka-Goetz, Magdalena (2021) Human embryo polarization requires PLC signaling to mediate trophectoderm specification. eLife, 10 . Art. No. e65068. ISSN 2050-084X. doi:10.7554/eLife.65068.

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Apico-basal polarization of cells within the embryo is critical for the segregation of distinct lineages during mammalian development. Polarized cells become the trophectoderm (TE), which forms the placenta, and apolar cells become the inner cell mass (ICM), the founding population of the fetus. The cellular and molecular mechanisms leading to polarization of the human embryo and its timing during embryogenesis have remained unknown. Here, we show that human embryo polarization occurs in two steps: it begins with the apical enrichment of F-actin and is followed by the apical accumulation of the PAR complex. This two-step polarization process leads to the formation of an apical domain at the 8–16 cell stage. Using RNA interference, we show that apical domain formation requires Phospholipase C (PLC) signaling, specifically the enzymes PLCB1 and PLCE1, from the eight-cell stage onwards. Finally, we show that although expression of the critical TE differentiation marker GATA3 can be initiated independently of embryo polarization, downregulation of PLCB1 and PLCE1 decreases GATA3 expression through a reduction in the number of polarized cells. Therefore, apical domain formation reinforces a TE fate. The results we present here demonstrate how polarization is triggered to regulate the first lineage segregation in human embryos.

Item Type:Article
Related URLs:
URLURL TypeDescription Paper
Zhu, Meng0000-0001-6157-8840
Shahbazi, Marta0000-0002-1599-5747
Zhang, Chuanxin0000-0003-0814-9275
Sozen, Berna0000-0001-5834-5819
Borsos, Mate0000-0002-2801-8910
Mandelbaum, Rachel S.0000-0001-8611-1462
Esbert, Marga0000-0002-0002-2272
Titus, Shiny0000-0002-8391-825X
Campbell, Alison0000-0002-4065-5672
Gradinaru, Viviana0000-0001-5868-348X
Seli, Emre0000-0001-7464-8203
Zernicka-Goetz, Magdalena0000-0002-7004-2471
Alternate Title:Mechanism of cell polarisation and first lineage segregation in the human embryo
Additional Information:© 2021, Zhu et al. This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited. Received: 20 November 2020; Accepted: 25 September 2021; Published: 27 September 2021. We are thankful to David Glover for comments on the manuscript, Marta Perez Sanchez, Antonia Weberling, Bailey Weatherbee, and Ali Ahmady for the help with human embryo culture, and to USC Fertility and HCLD for their support. M.Z. is funded by Leverhulme Trust. M.N.S. is funded by the European Molecular Biology Organization (EMBO) and the Medical Research Council (MRC, MC_UP_1201/24). Work in the laboratory of M.Z-G. on human embryos is funded by Wellcome Trust (207415/Z/17/Z), Open Philanthropy Grant, Curci, and Weston Havens Foundations. Work in the laboratory of Zi-Jiang Chen is funded by The National Key Research and Development Program of China (2018YFC1004000) and Shandong Provincial Key Research and Development Program (2018YFJH0504). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Author contributions: Meng Zhu, Marta Shahbazi, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review and editing; Angel Martin, Formal analysis, Investigation, Methodology, Validation, Visualization; Chuanxin Zhang, Berna Sozen, Mate Borsos, Marga Esbert, Shiny Titus, Investigation, Validation; Rachel S Mandelbaum, Investigation; Richard J Paulson, Resources, Supervision; Matteo A Mole, Investigation, Visualization; Richard T Scott, Alison Campbell, Simon Fishel, Keliang Wu, Resources; Viviana Gradinaru, Funding acquisition, Supervision; Han Zhao, Zi-Jiang Chen, Funding acquisition, Resources, Supervision; Emre Seli, Conceptualization, Funding acquisition, Resources, Supervision; Maria J de los Santos, Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Supervision; Magdalena Zernicka Goetz, Conceptualization, Funding acquisition, Methodology, Resources, Supervision, Writing – original draft, Writing – review and editing. Data availability: Source data files used for generating each figure has been uploaded as supplementary material.
Funding AgencyGrant Number
Leverhulme TrustUNSPECIFIED
European Molecular Biology Organization (EMBO)UNSPECIFIED
Medical Research Council (UK)MC_UP_1201/24
Wellcome Trust207415/Z/17/Z
Open PhilanthropyUNSPECIFIED
Shurl and Kay Curci FoundationUNSPECIFIED
Weston Havens FoundationUNSPECIFIED
National Key Research and Development Program of China2018YFC1004000
Shandong Provincial Key Research and Development Program2018YFJH0504
Subject Keywords:polarization, human embryo, cell fate, pre-implantation
Record Number:CaltechAUTHORS:20200925-104734056
Persistent URL:
Official Citation:Human embryo polarization requires PLC signaling to mediate trophectoderm specification. eLife 2021; 10:e65068; DOI: 10.7554/eLife.65068
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105548
Deposited By: George Porter
Deposited On:25 Sep 2020 20:25
Last Modified:14 Oct 2021 16:26

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