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Mechanism of cell polarisation and first lineage segregation in the human embryo

Zhu, Meng and Shahbazi, Marta N. 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 Scott, Richard T. and Campbell, Alison and Fishel, Simon and Gradinaru, Viviana and Zhao, Han and Wu, Keliang and Chen, Zijiang and Seli, Emre and de los Santos, Maria J. and Zernicka-Goetz, Magdalena (2020) Mechanism of cell polarisation and first lineage segregation in the human embryo. . (Unpublished)

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The formation of differential cell lineages in the mammalian blastocyst from the totipotent zygote is crucial for implantation and the success of the whole pregnancy. The first lineage segregation generates the polarised trophectoderm (TE) tissue, which forms the placenta, and the apolar inner cell mass (ICM), which mainly gives rise to all foetal tissues and also the yolk sac. The mechanism underlying this cell fate segregation has been extensively studied in the mouse embryo. However, when and how it takes place in the human embryo remains unclear. Here, using time-lapse imaging and 325 surplus human embryos, we provide a detailed characterisation of morphological events and transcription factor expression and localisation to understand how they lead to the first lineage segregation in human embryogenesis. We show that the first lineage segregation of the human embryo is triggered by cell polarisation that occurs at the 8-cell stage in two sequential steps. In the first step, F-actin becomes apically polarised concomitantly with embryo compaction. In the second step, the Par complex becomes polarised to form the apical cellular domain. Mechanistically, we show that activation of Phospholipase C (PLC) triggers actin polarisation and is therefore essential for apical domain formation, as is the case in mouse embryos. Finally, we show that, in contrast to the mouse embryo, the key extra-embryonic determinant GATA3 is expressed not only in extra-embryonic lineage precursors upon blastocyst formation. However, the cell polarity machinery enhances the expression and nuclear accumulation of GATA3. In summary, our results demonstrate for the first time that cell polarisation reinforces the first lineage segregation in the human embryo.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Zhu, Meng0000-0001-6157-8840
Shahbazi, Marta N.0000-0002-1599-5747
Zhang, Chuanxin0000-0003-0814-9275
Sozen, Berna0000-0001-5834-5819
Mandelbaum, Rachel S.0000-0001-8611-1462
Esbert, Marga0000-0002-0002-2272
Gradinaru, Viviana0000-0001-5868-348X
Seli, Emre0000-0001-7464-8203
Zernicka-Goetz, Magdalena0000-0002-7004-2471
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. We are thankful to David Glover for comments on the manuscript. We thank Marta Perez Sanchez , Antonia Weberling, Bailey Weatherbee and Ali Ahmady for the help with human embryo culture. We are grateful 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). Author contribution. M.Z., M.N.S., A.M. and M.J.S., designed and performed experiments and analysed the data. CX.Z. and M.B. performed microinjection experiments; M.A.M. performed an inhibitor treatment experiment. A.C., S.F., R.P. provided human embryos. E.S., R.T. S., M.N.S., M.J.S., R.S.M., Z-J.C. and H.Z. secured ethical approvals. B.S., M.E., KL. W., helped with experiments. Z-J.C., M.J.S., R.T.S. provided financial support. V.G. provided funding and supervision to M.B. M.Z., M.N.S. and M.Z-G. wrote the manuscript. M.Z-G. conceived and supervised the project, helped with data analyses and interpretation, and provided funding. Data availability. Data is available from the corresponding author upon request. The authors have declared no competing interest.
Funding AgencyGrant Number
European Molecular Biology Organization (EMBO)UNSPECIFIED
Medical Research Council (UK)MC_UP_1201/24
Wellcome Trust207415/Z/17/Z
Open PhilanthropyUNSPECIFIED
Curci FoundationUNSPECIFIED
Weston Havens FoundationUNSPECIFIED
National Key Research and Development Program of China2018YFC1004000
Shandong Provincial Key Research and Development Program2018YFJH0504
Subject Keywords:polarisation, human embryo, cell fate, pre-implantation
Record Number:CaltechAUTHORS:20200925-104734056
Persistent URL:
Official Citation:Mechanism of cell polarisation and first lineage segregation in the human embryo Meng Zhu, Marta N. Shahbazi, Angel Martin, Chuanxin Zhang, Berna Sozen, Mate Borsos, Rachel S. Mandelbaum, Richard J. Paulson, Matteo A. Mole, Marga Esbert, Richard T. Scott, Alison Campbell, Simon Fishel, Viviana Gradinaru, Han Zhao, Keliang Wu, Zijiang Chen, Emre Seli, Maria J. de los Santos, Magdalena Zernicka-Goetz bioRxiv 2020.09.23.310680; doi:
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:25 Sep 2020 20:25

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