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Nature. 2017 Mar 23;543(7646):568-572. doi: 10.1038/nature21690. Epub 2017 Mar 15.

DND1 maintains germline stem cells via recruitment of the CCR4-NOT complex to target mRNAs.

Author information

1
Howard Hughes Medical Institute and Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Ave, Box 186, New York, New York 10065, USA.
2
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.
3
Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer Building, Bronx, New York, New York 10461, USA.
4
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute for Arthritis and Musculoskeletal and Skin Disease, 50 South Drive, MSC 8024, Bethesda, Maryland 20892, USA.

Abstract

The vertebrate-conserved RNA-binding protein DND1 is required for the survival of primordial germ cells (PGCs), as well as the suppression of germ cell tumours in mice. Here we show that in mice DND1 binds a UU(A/U) trinucleotide motif predominantly in the 3' untranslated regions of mRNA, and destabilizes target mRNAs through direct recruitment of the CCR4-NOT deadenylase complex. Transcriptomic analysis reveals that the extent of suppression is dependent on the number of DND1-binding sites. This DND1-dependent mRNA destabilization is required for the survival of mouse PGCs and spermatogonial stem cells by suppressing apoptosis. The spectrum of target RNAs includes positive regulators of apoptosis and inflammation, and modulators of signalling pathways that regulate stem-cell pluripotency, including the TGFβ superfamily, all of which are aberrantly elevated in DND1-deficient PGCs. We propose that the induction of the post-transcriptional suppressor DND1 synergizes with concurrent transcriptional changes to ensure precise developmental transitions during cellular differentiation and maintenance of the germ line.

PMID:
28297718
PMCID:
PMC5488729
DOI:
10.1038/nature21690
[Indexed for MEDLINE]
Free PMC Article

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