Progression of the pluripotent epiblast depends upon the NMD factor UPF2

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  • Jennifer N. Chousal
  • Abhishek Sohni
  • Kristoffer Vitting-Seerup
  • Kyucheol Cho
  • Matthew Kim
  • Kun Tan
  • Porse, Bo Torben
  • Miles F. Wilkinson
  • Heidi Cook-Andersen
Nonsense-mediated RNA decay (NMD) is a highly conserved RNA turnover pathway that degrades RNAs harboring in-frame stop codons in specific contexts. Loss of NMD factors leads to embryonic lethality in organisms spanning the phylogenetic scale, but the mechanism remains unknown. Here, we report that the core NMD factor, UPF2, is required for expansion of epiblast cells within the inner cell mass of mice in vivo. We identify NMD target mRNAs in mouse blastocysts – both canonical and alternatively processed mRNAs – including those encoding cell cycle arrest and apoptosis factors, raising the possibility that NMD is essential for embryonic cell proliferation and survival. In support, the inner cell mass of Upf2-null blastocysts rapidly regresses with outgrowth and is incompetent for embryonic stem cell derivation in vitro. In addition, we uncovered concordant temporal- and lineage-specific regulation of NMD factors and mRNA targets, indicative of a shift in NMD magnitude during peri-implantation development. Together, our results reveal developmental and molecular functions of the NMD pathway in the early embryo.
OriginalsprogEngelsk
Artikelnummerdev200764
TidsskriftDevelopment
Vol/bind149
Udgave nummer21
Antal sider15
ISSN0950-1991
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
This work was supported by the National Institutes of Health R01 HD093846. H.C.-A. was also supported by the Burroughs Wellcome Fund Career Award for Medical Scientists and the National Institutes of Health R01 GM124519 and K12 HD007203. Work in the Porse lab was supported by a grant from the Novo Nordisk Fonden (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; NNF17CC0027852). Open Access funding provided by University of California San Diego. Deposited in PMC for immediate release.

Funding Information:
We thank all members of the laboratory for helpful feedback during the project. We thank the Nikon Imaging Center for help with image acquisition, analysis and processing, as well as Kristen Jepsen and members of the IGM Core for their assistance with sequencing. This work was supported by the National Institutes of Health R01 HD093846. H.C.-A. was also supported by the Burroughs Wellcome Fund Career Award for Medical Scientists and the National Institutes of Health R01 GM124519 and K12 HD007203. Work in the Porse lab was supported by a grant from the Novo Nordisk Fonden (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; NNF17CC0027852). Open Access funding provided by University of California San Diego. Deposited in PMC for immediate release.

Publisher Copyright:
© 2022. Published by The Company of Biologists Ltd.

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