Abstract
Current understandings of cell specification in early mammalian pre-implantation development are based mainly on mouse studies. The first lineage differentiation event occurs at the morula stage, with outer cells initiating a trophectoderm (TE) placental progenitor program. The inner cell mass arises from inner cells during subsequent developmental stages and comprises precursor cells of the embryo proper and yolk sac1. Recent gene-expression analyses suggest that the mechanisms that regulate early lineage specification in the mouse may differ in other mammals, including human2-5 and cow6. Here we show the evolutionary conservation of a molecular cascade that initiates TE segregation in human, cow and mouse embryos. At the morula stage, outer cells acquire an apical-basal cell polarity, with expression of atypical protein kinase C (aPKC) at the contact-free domain, nuclear expression of Hippo signalling pathway effectors and restricted expression of TE-associated factors such as GATA3, which suggests initiation of a TE program. Furthermore, we demonstrate that inhibition of aPKC by small-molecule pharmacological modulation or Trim-Away protein depletion impairs TE initiation at the morula stage. Our comparative embryology analysis provides insights into early lineage specification and suggests that a similar mechanism initiates a TE program in human, cow and mouse embryos.
| Original language | English |
|---|---|
| Pages (from-to) | 443-447 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 587 |
| Issue number | 7834 |
| Early online date | 23 Sep 2020 |
| DOIs | |
| Publication status | Published - Nov 2020 |
Bibliographical note
Funding Information:Acknowledgements We thank the donors whose contributions have enabled this research; P. Patel, A. Srikantharajah, M. Summers, A. Handyside, K. Ahuja, S. Lavery, A. Rattos and M. Jansa Perez for the coordination and donation of embryos to our research project; members of the laboratories of K.K.N., J. M. A. Turner and R. Lovell-Badge, as well as M. Marass, T. Rayon Alonso, B. Thompson and N. Goehring for discussion, advice and feedback on the manuscript; the laboratories of B. Thompson, N. Goehring and J. Briscoe for sharing reagents and advice; the Advanced Light Microscopy and Biological Research Facilities (Francis Crick Institute); and A. Brodie and K. Bacon for assisting with cow embryo culture. The AMOT antibody (Amot-C no. 10061-1) used in this paper for mouse embryos was provided by the laboratory of H. Sasaki. CRT0276121 was provided by Cancer Research Technology. Work in the laboratory of L.D. was funded by a donation from MSD to ‘Fondation de l’Université de Nantes’. Work in the laboratory of H.V.d.V. was funded by the Fonds Wetenschappelijk Onderzoek Flanders (FWOAL722) and the Wetenschappelijk Fonds Willy Gepts (WFWG, UZ Brussel, G142). Work in the laboratory of A.A.F.-N. was supported by Comparative Biomedical Sciences Departmental fund from the Royal Veterinary College. Work in the laboratory of K.K.N. was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001120), the UK Medical Research Council (FC001120) and the Wellcome Trust (FC001120), and by the Rosa Beddington Fund.
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