title: DND1 maintains germline stem cells via recruitment of the CCR4-NOT complex to target mRNAs.
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.
authors.affiliation: Howard Hughes Medical Institute and Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Ave, Box 186, New York, New York 10065, USA.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamaji
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.
authors.forename: Miki
authors.initials: M
authors.lastname: Jishage
authors.affiliation: Howard Hughes Medical Institute and Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Ave, Box 186, New York, New York 10065, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Howard Hughes Medical Institute and Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Ave, Box 186, New York, New York 10065, USA.
authors.forename: Hemant
authors.initials: H
authors.lastname: Suryawanshi
authors.affiliation: Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer Building, Bronx, New York, New York 10461, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Der
authors.affiliation: Howard Hughes Medical Institute and Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Ave, Box 186, New York, New York 10065, USA.
authors.forename: Misaki
authors.initials: M
authors.lastname: Yamaji
authors.affiliation: Howard Hughes Medical Institute and Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Ave, Box 186, New York, New York 10065, USA.
authors.forename: Aitor
authors.initials: A
authors.lastname: Garzia
authors.affiliation: Howard Hughes Medical Institute and Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Ave, Box 186, New York, New York 10065, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Morozov
authors.affiliation: 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.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Manickavel
authors.affiliation: 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.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: McFarland
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.affiliation: 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.
authors.forename: Markus
authors.initials: M
authors.lastname: Hafner
authors.affiliation: Howard Hughes Medical Institute and Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Ave, Box 186, New York, New York 10065, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008297:Male; D051379:Mice; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000378:metabolism*; D059372:Nucleotide Motifs; D039904:Pluripotent Stem Cells / Q000166:cytology; D011485:Protein Binding; D020871:RNA Stability; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012260:Ribonucleases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013093:Spermatogonia / Q000166:cytology* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; C500862:Dnd1 protein, mouse; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D012260:Ribonucleases; C445084:mRNA deadenylase