DND1 Maintains Germline Stem Cells Via Recruitment of the CCR4-NOT Complex to Target MRNAs

Overview

Journal Nature

Specialty Science

Date 2017 Mar 16

PMID 28297718

Citations 80

Authors

Masashi Yamaji

Miki Jishage

Cindy Meyer

Hemant Suryawanshi

Evan Der

Misaki Yamaji

Aitor Garzia

Pavel Morozov

Sudhir Manickavel

Hannah L McFarland

Robert G Roeder

Markus Hafner

Thomas Tuschl

Affiliations

Soon will be listed here.

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.

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References

Macosko E, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M . Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell. 2015; 161(5):1202-1214. PMC: 4481139. DOI: 10.1016/j.cell.2015.05.002. View

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

Kuwasako K, Takahashi M, Tochio N, Abe C, Tsuda K, Inoue M . Solution structure of the second RNA recognition motif (RRM) domain of murine T cell intracellular antigen-1 (TIA-1) and its RNA recognition mode. Biochemistry. 2008; 47(24):6437-50. DOI: 10.1021/bi7024723. View

Kanatsu-Shinohara M, Ogonuki N, Inoue K, Miki H, Ogura A, Toyokuni S . Long-term proliferation in culture and germline transmission of mouse male germline stem cells. Biol Reprod. 2003; 69(2):612-6. DOI: 10.1095/biolreprod.103.017012. View

Sakurai T, Iguchi T, Moriwaki K, Noguchi M . The ter mutation first causes primordial germ cell deficiency in ter/ter mouse embryos at 8 days of gestation. Dev Growth Differ. 2023; 37(3):293-302. DOI: 10.1046/j.1440-169X.1995.t01-2-00007.x. View

Kurimoto K, Yabuta Y, Hayashi K, Ohta H, Kiyonari H, Mitani T . Quantitative Dynamics of Chromatin Remodeling during Germ Cell Specification from Mouse Embryonic Stem Cells. Cell Stem Cell. 2015; 16(5):517-32. DOI: 10.1016/j.stem.2015.03.002. View

Huang D, Sherman B, Lempicki R . Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2008; 37(1):1-13. PMC: 2615629. DOI: 10.1093/nar/gkn923. View

Chen X, Xu F, Zhu C, Ji J, Zhou X, Feng X . Dual sgRNA-directed gene knockout using CRISPR/Cas9 technology in Caenorhabditis elegans. Sci Rep. 2014; 4:7581. PMC: 4273605. DOI: 10.1038/srep07581. View

Spiller C, Feng C, Jackson A, Gillis A, Rolland A, Looijenga L . Endogenous Nodal signaling regulates germ cell potency during mammalian testis development. Development. 2012; 139(22):4123-32. DOI: 10.1242/dev.083006. View

10.

Ran F, Hsu P, Wright J, Agarwala V, Scott D, Zhang F . Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013; 8(11):2281-2308. PMC: 3969860. DOI: 10.1038/nprot.2013.143. View

11.

Yabuta Y, Kurimoto K, Ohinata Y, Seki Y, Saitou M . Gene expression dynamics during germline specification in mice identified by quantitative single-cell gene expression profiling. Biol Reprod. 2006; 75(5):705-16. DOI: 10.1095/biolreprod.106.053686. View

12.

Youngren K, Coveney D, Peng X, Bhattacharya C, Schmidt L, Nickerson M . The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours. Nature. 2005; 435(7040):360-4. PMC: 1421521. DOI: 10.1038/nature03595. View

13.

Roers A, Hiller B, Hornung V . Recognition of Endogenous Nucleic Acids by the Innate Immune System. Immunity. 2016; 44(4):739-54. DOI: 10.1016/j.immuni.2016.04.002. View

14.

Mukherjee N, Corcoran D, Nusbaum J, Reid D, Georgiev S, Hafner M . Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability. Mol Cell. 2011; 43(3):327-39. PMC: 3220597. DOI: 10.1016/j.molcel.2011.06.007. View

15.

Rouya C, Siddiqui N, Morita M, Duchaine T, Fabian M, Sonenberg N . Human DDX6 effects miRNA-mediated gene silencing via direct binding to CNOT1. RNA. 2014; 20(9):1398-409. PMC: 4138323. DOI: 10.1261/rna.045302.114. View

16.

Kedde M, Strasser M, Boldajipour B, Vrielink J, Slanchev K, le Sage C . RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell. 2007; 131(7):1273-86. DOI: 10.1016/j.cell.2007.11.034. View

17.

Suzuki A, Igarashi K, Aisaki K, Kanno J, Saga Y . NANOS2 interacts with the CCR4-NOT deadenylation complex and leads to suppression of specific RNAs. Proc Natl Acad Sci U S A. 2010; 107(8):3594-9. PMC: 2840499. DOI: 10.1073/pnas.0908664107. View

18.

Slanchev K, Stebler J, Goudarzi M, Cojocaru V, Weidinger G, Raz E . Control of Dead end localization and activity--implications for the function of the protein in antagonizing miRNA function. Mech Dev. 2008; 126(3-4):270-7. DOI: 10.1016/j.mod.2008.10.006. View

19.

Sievers F, Wilm A, Dineen D, Gibson T, Karplus K, Li W . Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011; 7:539. PMC: 3261699. DOI: 10.1038/msb.2011.75. View

20.

Al-Zoghaibi F, Ashour T, Al-Ahmadi W, Abulleef H, Demirkaya O, Khabar K . Bioinformatics and experimental derivation of an efficient hybrid 3' untranslated region and use in expression active linear DNA with minimum poly(A) region. Gene. 2007; 391(1-2):130-9. DOI: 10.1016/j.gene.2006.12.013. View