The DNA damage response is required for oocyte cyst breakdown and follicle formation in mice

English version

Autoři: Ana Martínez-Marchal ^aff001; Yan Huang ^aff001; Maria Teresa Guillot-Ferriols ^aff001; Mònica Ferrer-Roda ^aff001; Anna Guixé ^aff001; Montserrat Garcia-Caldés ^aff002; Ignasi Roig ^aff001
Působiště autorů: Unitat de Citologia i Histologia, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain ^aff001; Grup d’Inestabilitat i Integritat del genoma, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain ^aff002; Unitat de Biologia Cel·lular i Genètica Mèdica, Facultat de Medicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain ^aff003
Vyšlo v časopise: The DNA damage response is required for oocyte cyst breakdown and follicle formation in mice. PLoS Genet 16(11): e1009067. doi:10.1371/journal.pgen.1009067
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009067

Souhrn

Mammalian oogonia proliferate without completing cytokinesis, forming cysts. Within these, oocytes differentiate and initiate meiosis, promoting double-strand break (DSBs) formation, which are repaired by homologous recombination (HR) causing the pairing and synapsis of the homologs. Errors in these processes activate checkpoint mechanisms, leading to apoptosis. At the end of prophase I, in contrast with what is observed in spermatocytes, oocytes accumulate unrepaired DSBs. Simultaneously to the cyst breakdown, there is a massive oocyte death, which has been proposed to be necessary to enable the individualization of the oocytes to form follicles. Based upon all the above-mentioned information, we hypothesize that the apparently inefficient HR occurring in the oocytes may be a requirement to first eliminate most of the oocytes and enable cyst breakdown and follicle formation. To test this idea, we compared perinatal ovaries from control and mutant mice for the effector kinase of the DNA Damage Response (DDR), CHK2. We found that CHK2 is required to eliminate ~50% of the fetal oocyte population. Nevertheless, the number of oocytes and follicles found in Chk2-mutant ovaries three days after birth was equivalent to that of the controls. These data revealed the existence of another mechanism capable of eliminating oocytes. In vitro inhibition of CHK1 rescued the oocyte number in Chk2^-/- mice, implying that CHK1 regulates postnatal oocyte death. Moreover, we found that CHK1 and CHK2 functions are required for the timely breakdown of the cyst and to form follicles. Thus, we uncovered a novel CHK1 function in regulating the oocyte population in mice. Based upon these data, we propose that the CHK1 -⁠ and CHK2-dependent DDR controls the number of oocytes and is required to properly break down oocyte cysts and form follicles in mammals.

Klíčová slova:

Birth – DNA damage – DNA repair – Fetal development – Mammalian genomics – Meiotic prophase – Oocytes – Ovaries

Zdroje

1. Molyneaux KA, Stallock J, Schaible K, Wylie C. Time-Lapse Analysis of Living Mouse Germ Cell Migration. Dev Biol. 2001;240 : 488–498. doi: 10.1006/dbio.2001.0436 11784078

2. McLaren A. Meiosis and differentiation of mouse germ cells. Symp Soc Exp Biol. 1984;38 : 7–23. 6400220

3. Pepling ME, Spradling AC. Female mouse germ cells form synchronously dividing cysts. Development. 1998;125 : 3323–8. 9693136

4. Tam PP, Snow MH. Proliferation and migration of primordial germ cells during compensatory growth in mouse embryos. J Embryol Exp Morphol. 1981;64 : 133–47. 7310300

5. Borum K. Oogenesis in the mouse. Exp Cell Res. 1961;24 : 495–507. doi: 10.1016/0014-4827(61)90449-9 13871511

6. Hirshfield AN. Development of follicles in the mammalian ovary. Int Rev Cytol. 1991;124 : 43–101. doi: 10.1016/s0074-7696(08)61524-7 2001918

7. Klinger FG, Rossi V, De Felici M. Multifaceted programmed cell death in the mammalian fetal ovary. Int J Dev Biol. 2015;59 : 51–54. doi: 10.1387/ijdb.150063fk 26374525

8. Baker TG. A quantitative and cytological study of germ cells in human ovaries. Proc R Soc Lond Biol. 1963;158 : 417–433. doi: 10.1098/rspb.1963.0055 14070052

9. Pepling ME. Follicular assembly: mechanisms of action. REPRODUCTION. 2012;143 : 139–149. doi: 10.1530/REP-11-0299 22065859

10. Pepling ME, Spradling AC. Mouse ovarian germ cell cysts undergo programmed breakdown to form primordial follicles. Dev Biol. 2001;234 : 339–351. doi: 10.1006/dbio.2001.0269 11397004

11. Malki S, van der Heijden GW, O’Donnell KA, Martin SL, Bortvin A. A Role for Retrotransposon LINE-1 in Fetal Oocyte Attrition in Mice. Dev Cell. 2014;29 : 521–533. doi: 10.1016/j.devcel.2014.04.027 24882376

12. Hunter N. Oocyte Quality Control: Causes, Mechanisms, and Consequences. Cold Spring Harb Symp Quant Biol. 2017;82 : 235–247. doi: 10.1101/sqb.2017.82.035394 29743337

13. Baudat F, Manova K, Yuen JP, Jasin M, Keeney S. Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Mol Cell. 2000;6 : 989–998. doi: 10.1016/s1097-2765(00)00098-8 11106739

14. Subramanian V V, Hochwagen A. The Meiotic Checkpoint Network: Step-by-Step through Meiotic Prophase. Cold Spring Harb Perspect Biol. 2014;6. doi: 10.1101/cshperspect.a016675 25274702

15. Di Giacomo M, Barchi M, Baudat F, Edelmann W, Keeney S, Jasin M. Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants. Proc Natl Acad Sci U S A. 2005;102 : 737–742. doi: 10.1073/pnas.0406212102 15640358

16. Barchi M, Mahadevaiah S, Di Giacomo M, Baudat F, de Rooij DG, Burgoyne PS, et al. Surveillance of different recombination defects in mouse spermatocytes yields distinct responses despite elimination at an identical developmental stage. Mol Cell Biol. 2005;25 : 7203–7215. doi: 10.1128/MCB.25.16.7203-7215.2005 16055729

17. Pacheco S, Marcet-Ortega M, Lange J, Jasin M, Keeney S, Roig I. The ATM Signaling Cascade Promotes Recombination-Dependent Pachytene Arrest in Mouse Spermatocytes. Lichten M, editor. PLOS Genet. 2015;11: e1005017. doi: 10.1371/journal.pgen.1005017 25768017

18. Marcet-Ortega M, Pacheco S, Martínez-Marchal A, Castillo H, Flores E, Jasin M, et al. p53 and TAp63 participate in the recombination-dependent pachytene arrest in mouse spermatocytes. Cohen PE, editor. PLoS Genet. 2017;13: e1006845. doi: 10.1371/journal.pgen.1006845 28617799

19. Bolcun-Filas E, Rinaldi VD, White ME, Schimenti JC. Reversal of Female Infertility by Chk2 Ablation Reveals the Oocyte DNA Damage Checkpoint Pathway. Science (80-). 2014;343 : 533–536. doi: 10.1126/science.1247671 24482479

20. Stracker TH, Usui T, Petrini JHJ. Taking the time to make important decisions: the checkpoint effector kinases Chk1 and Chk2 and the DNA damage response. DNA Repair (Amst). 2009;8 : 1047–1054. doi: 10.1016/j.dnarep.2009.04.012 19473886

21. Barchi M, Roig I, Di Giacomo M, De Rooij DGG, Keeney S, Jasin M. ATM promotes the obligate XY crossover and both crossover control and chromosome axis integrity on autosomes. PLoS Genet. 2008;4: e1000076. doi: 10.1371/journal.pgen.1000076 18497861

22. Pacheco S, Maldonado-Linares A, Marcet-Ortega M, Rojas C, Martínez-Marchal A, Fuentes-Lazaro J, et al. ATR is required to complete meiotic recombination in mice. Nat Commun. 2018;9 : 2622. doi: 10.1038/s41467-018-04851-z 29977027

23. Abe H, Alavattam KG, Kato Y, Castrillon DH, Pang Q, Andreassen PR, et al. CHEK1 coordinates DNA damage signaling and meiotic progression in the male germline of mice. Hum Mol Genet. 2018;27 : 1136–1149. doi: 10.1093/hmg/ddy022 29360988

24. Widger A, Mahadevaiah SK, Lange J, ElInati E, Zohren J, Hirota T, et al. ATR is a multifunctional regulator of male mouse meiosis. Nat Commun. 2018;9 : 2621. doi: 10.1038/s41467-018-04850-0 29976923

25. Morelli MA, Cohen PE. Not all germ cells are created equal: aspects of sexual dimorphism in mammalian meiosis. Reproduction. 2005;130 : 761–781. doi: 10.1530/rep.1.00865 16322537

26. Roig I, Liebe B, Egozcue J, Cabero L, Garcia M, Scherthan H. Female-specific features of recombinational double-stranded DNA repair in relation to synapsis and telomere dynamics in human oocytes. Chromosoma. 2004;113 : 22–33. doi: 10.1007/s00412-004-0290-8 15235794

27. Lenzi ML, Smith J, Snowden T, Kim M, Fishel R, Poulos BK, et al. Extreme heterogeneity in the molecular events leading to the establishment of chiasmata during meiosis I in human oocytes. Am J Hum Genet. 2005;76 : 112–127. doi: 10.1086/427268 15558497

28. Pacheco S, Maldonado-Linares A, Garcia-Caldés M, Roig I. ATR function is indispensable to allow proper mammalian follicle development. Chromosoma. 2019;128 : 489–500 doi: 10.1007/s00412-019-00723-7 31489491

29. Qiao H, Rao HBDP, Yun Y, Sandhu S, Fong JH, Sapre M, et al. Impeding DNA Break Repair Enables Oocyte Quality Control. Mol Cell. 2018;72 : 211–221.e3. doi: 10.1016/j.molcel.2018.08.031 30270110

30. Takai H, Naka K, Okada Y, Watanabe M, Harada N, Saito S, et al. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J. 2002;21 : 5195–5205. doi: 10.1093/emboj/cdf506 12356735

31. Carofiglio F, Inagaki A, de Vries S, Wassenaar E, Schoenmakers S, Vermeulen C, et al. SPO11-Independent DNA Repair Foci and Their Role in Meiotic Silencing. PLoS Genet. 2013;9: e1003538. doi: 10.1371/journal.pgen.1003538 23754961

32. Rinaldi VD, Bolcun-Filas E, Kogo H, Kurahashi H, Schimenti JC. The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure. Mol Cell. 2017;67 : 1026–1036.e2. doi: 10.1016/j.molcel.2017.07.027 28844861

33. Dai Y, Grant S. New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res. 2010;16 : 376–83. doi: 10.1158/1078-0432.CCR-09-1029 20068082

34. Belgnaoui SM, Gosden RG, Semmes OJ, Haoudi A. Human LINE-1 retrotransposon induces DNA damage and apoptosis in cancer cells. Cancer Cell Int. 2006;6 : 13. doi: 10.1186/1475-2867-6-13 16670018

35. Mahadevaiah SK, Bourc’his D, de Rooij DG, Bestor TH, Turner JM, Burgoyne PS. Extensive meiotic asynapsis in mice antagonises meiotic silencing of unsynapsed chromatin and consequently disrupts meiotic sex chromosome inactivation. J Cell Biol. 2008;182 : 263–276. doi: 10.1083/jcb.200710195 18663141

36. Turner JM, Mahadevaiah SK, Fernandez-Capetillo O, Nussenzweig A, Xu X, Deng CX, et al. Silencing of unsynapsed meiotic chromosomes in the mouse. Nat Genet. 2005;37 : 41–47. doi: 10.1038/ng1484 15580272

37. Ichijima Y, Sin H-S, Namekawa SH. Sex chromosome inactivation in germ cells: emerging roles of DNA damage response pathways. Cell Mol Life Sci. 2012;69 : 2559–2572. doi: 10.1007/s00018-012-0941-5 22382926

38. Ichijima Y, Ichijima M, Lou Z, Nussenzweig A, Camerini-Otero RD, Chen J, et al. MDC1 directs chromosome-wide silencing of the sex chromosomes in male germ cells. Genes Dev. 2011;25 : 959–71. doi: 10.1101/gad.2030811 21536735

39. Cloutier JM, Mahadevaiah SK, ElInati E, Nussenzweig A, Tóth A, Turner JMA. Histone H2AFX Links Meiotic Chromosome Asynapsis to Prophase I Oocyte Loss in Mammals. PLoS Genet. 2015;11: e1005462. doi: 10.1371/journal.pgen.1005462 26509888

40. Royo H, Prosser H, Ruzankina Y, Mahadevaiah SK, Cloutier JM, Baumann M, et al. ATR acts stage specifically to regulate multiple aspects of mammalian meiotic silencing. Genes Dev. 2013;27 : 1484–1494. doi: 10.1101/gad.219477.113 23824539

41. Rinaldi VD, Bloom JC, Schimenti JC. Oocyte Elimination Through DNA Damage Signaling from CHK1/CHK2 to p53 and p63. Genetics. 2020;215 : 373–378. doi: 10.1534/genetics.120.303182 32273296

42. ElInati E, Zielinska AP, McCarthy A, Kubikova N, Maciulyte V, Mahadevaiah S, et al. The BCL-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes. Nat Commun. 2020;11 : 2598. doi: 10.1038/s41467-020-16441-z 32451402

43. Malki S, van der Heijden GW, O’Donnell KA, Martin SL, Bortvin A. A Role for Retrotransposon LINE-1 in Fetal Oocyte Attrition in Mice. Dev Cell. 2019;51 : 658. doi: 10.1016/j.devcel.2019.11.011 31794719

44. Tharp ME, Malki S, Bortvin A. Maximizing the ovarian reserve in mice by evading LINE-1 genotoxicity. Nat Commun. 2020;11 : 330. doi: 10.1038/s41467-019-14055-8 31949138

45. Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, et al. Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev. 2000;14 : 1448–1459. 10859164

46. Suh EK, Yang A, Kettenbach A, Bamberger C, Michaelis AH, Zhu Z, et al. p63 protects the female germ line during meiotic arrest. Nature. 2006;444 : 624–628. doi: 10.1038/nature05337 17122775

47. Kim D-A, Suh E-K. Defying DNA Double-Strand Break-Induced Death during Prophase I Meiosis by Temporal TAp63 Phosphorylation Regulation in Developing Mouse Oocytes. Mol Cell Biol. 2014;34 : 1460–1473. doi: 10.1128/MCB.01223-13 24515437

48. Pepling ME. From primordial germ cell to primordial follicle: mammalian female germ cell development. Genes (New York, NY 2000). 2006;44 : 622–632. doi: 10.1002/dvg.20258 17146778

49. Xu J, Gridley T. Notch2 is required in somatic cells for breakdown of ovarian germ-cell nests and formation of primordial follicles. BMC Biol. 2013;11 : 13. doi: 10.1186/1741-7007-11-13 23406467

50. Lei L, Spradling AC. Mouse primordial germ cells produce cysts that partially fragment prior to meiosis. Development. 2013;140 : 2075–81. doi: 10.1242/dev.093864 23578925

51. Morgan S, Campbell L, Allison V, Murray A, Spears N. Culture and co-culture of mouse ovaries and ovarian follicles. J Vis Exp. 2015; 17 : 52458. doi: 10.3791/52458 25867892

Článek A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population

Článek Mms19 promotes spindle microtubule assembly in Drosophila neural stem cells

Článek Formal commentary

Článek Loss of hepatocyte cell division leads to liver inflammation and fibrosis

Článek A genetic variant controls interferon-β gene expression in human myeloid cells by preventing C/EBP-β binding on a conserved enhancer

Článek A proteomic survey of microtubule-associated proteins in a R402H TUBA1A mutant mouse

Článek Inferring causal direction between two traits in the presence of horizontal pleiotropy with GWAS summary data

Článek A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease

Článek Unique genetic signatures of local adaptation over space and time for diapause, an ecologically relevant complex trait, in Drosophila melanogaster

Článek The Bric-à-Brac BTB/POZ transcription factors are necessary in niche cells for germline stem cells establishment and homeostasis through control of BMP/DPP signaling in the Drosophila melanogaster ovary

Článek No association between SCN9A and monogenic human epilepsy disorders

Článek Genome-wide association study identifies 16 genomic regions associated with circulating cytokines at birth