TY - JOUR

T1 - Progression of the pluripotent epiblast depends upon the NMD factor UPF2

AU - Chousal, Jennifer N.

AU - Sohni, Abhishek

AU - Vitting-Seerup, Kristoffer

AU - Cho, Kyucheol

AU - Kim, Matthew

AU - Tan, Kun

AU - Porse, Bo

AU - Wilkinson, Miles F.

AU - Cook-Andersen, Heidi

N1 - Publisher Copyright: © 2022. Published by The Company of Biologists Ltd.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - Blastocyst

KW - Epiblast

KW - Nonsense-mediated RNA decay

KW - RNA decay

U2 - 10.1242/dev.200764

DO - 10.1242/dev.200764

M3 - Journal article

C2 - 36255229

AN - SCOPUS:85144185696

VL - 149

JO - Development

JF - Development

SN - 0950-1991

IS - 21

M1 - dev200764

ER -