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Nature communications
01 16, 2020;11 (1): 330.

Maximizing the ovarian reserve in mice by evading LINE-1 genotoxicity.

Marla E Tharp, Safia Malki, Alex Bortvin
Author Information
  1. Marla E Tharp: Department of Embryology, Carnegie Institution for Science, Baltimore, MD, 21218, USA.
  2. Safia Malki: Department of Embryology, Carnegie Institution for Science, Baltimore, MD, 21218, USA.
  3. Alex Bortvin: Department of Embryology, Carnegie Institution for Science, Baltimore, MD, 21218, USA. bortvin@carnegiescience.edu. ORCID
PMID: 31949138 DOI: 10.1038/s41467-019-14055-8

Abstract

Female reproductive success critically depends on the size and quality of a finite ovarian reserve. Paradoxically, mammals eliminate up to 80% of the initial oocyte pool through the enigmatic process of fetal oocyte attrition (FOA). Here, we interrogate the striking correlation of FOA with retrotransposon LINE-1 (L1) expression in mice to understand how L1 activity influences FOA and its biological relevance. We report that L1 activity triggers FOA through DNA damage-driven apoptosis and the complement system of immunity. We demonstrate this by combined inhibition of L1 reverse transcriptase activity and the Chk2-dependent DNA damage checkpoint to prevent FOA. Remarkably, reverse transcriptase inhibitor AZT-treated Chk2 mutant oocytes that evade FOA initially accumulate, but subsequently resolve, L1-instigated genotoxic threats independent of piRNAs and differentiate, resulting in an increased functional ovarian reserve. We conclude that FOA serves as quality control for oocyte genome integrity, and is not obligatory for oogenesis nor fertility.

References

  1. Greenspan, L. J., de Cuevas, M. & Matunis, E. Genetics of gonadal stem cell renewal. Annu. Rev. Cell Dev. Biol. 31, 291���315 (2015). [PMID: 26355592]
  2. Lei, L. & Spradling, A. C. Female mice lack adult germ-line stem cells but sustain oogenesis using stable primordial follicles. Proc. Natl Acad. Sci. USA 110, 8585���8590 (2013). [PMID: 23630252]
  3. Zhang, H. et al. Experimental evidence showing that no mitotically active female germline progenitors exist in postnatal mouse ovaries. Proc. Natl Acad. Sci. USA 109, 12580���12585 (2012). [PMID: 22778414]
  4. Hanna, C. B. & Hennebold, J. D. Ovarian germline stem cells: an unlimited source of oocytes? Fertil. Steril. 101, 20���30 (2014). [PMID: 24382341]
  5. Pelosi, E., Simonsick, E., Forabosco, A., Garcia-Ortiz, J. E. & Schlessinger, D. Dynamics of the ovarian reserve and impact of genetic and epidemiological factors on age of menopause. Biol. Reprod. 92, 130 (2015). [PMID: 25904009]
  6. Grive, K. J. & Freiman, R. N. The developmental origins of the mammalian ovarian reserve. Development 142, 2554���2563 (2015). [PMID: 26243868]
  7. Pelosi, E., Forabosco, A. & Schlessinger, D. Genetics of the ovarian reserve. Front. Genet. 6, 308 (2015). [PMID: 26528328]
  8. Findlay, J. K., Hutt, K. J., Hickey, M. & Anderson R. A. What is the "ovarian reserve"? Fertil. Steril. 103, 628���630 (2014).
  9. Baker, T. G. A quantitative and cytological study of germ cells in human ovaries. Proc. R. Soc. Lond. B 158, 417���433 (1963). [PMID: 14070052]
  10. Kurilo, L. F. Oogenesis in antenatal development in man. Hum. Genet. 57, 86���92 (1981). [PMID: 7262874]
  11. Baker, T. G. A quantitative and cytological study of oogenesis in the rhesus monkey. J. Anat. 100, 761���776 (1966). [PMID: 4961727]
  12. Beaumont, H. M. & Mandl, A. M. A quantitative and cytological study of oognonia and oocytes in the foetal and nonatal rat. Proc. R. Soc. Lond. B 155, 557���579 (1962). [DOI: 10.1098/rspb.1962.0019]
  13. Burgoyne, P. S. & Baker, T. G. Perinatal oocyte loss in XO mice and its implications for the aetiology of gonadal dysgenesis in XO women. J. Reprod. Fertil. 75, 633���645 (1985). [PMID: 3906118]
  14. Ioannou, J. M. Ooegenesis in the guinea-pig. J. Embryol. Exp. Morphol. 12, 673���691 (1964). [PMID: 14251479]
  15. Tilly, J. L. Commuting the death sentence: how oocytes strive to survive. Nat. Rev. Mol. Cell Biol. 2, 838���848 (2001). [PMID: 11715050]
  16. Hartshorne, G. M., Lyrakou, S., Hamoda, H., Oloto, E. & Ghafari, F. Oogenesis and cell death in human prenatal ovaries: what are the criteria for oocyte selection? Mol. Hum. Reprod. 15, 805���819 (2009). [PMID: 19584195]
  17. Pepling, M. E. & Spradling, A. C. Mouse ovarian germ cell cysts undergo programmed breakdown to form primordial follicles. Dev. Biol. 234, 339���351 (2001). [PMID: 11397004]
  18. Malki, S., van der Heijden, G. W., O'Donnell, K. A., Martin, S. L. & Bortvin, A. A role for retrotransposon LINE-1 in fetal oocyte attrition in mice. Dev. Cell 29, 521���533 (2014). [PMID: 24882376]
  19. Venter, J. C. et al. The sequence of the human genome. Science 291, 1304���1351 (2001). [DOI: 10.1126/science.1058040]
  20. Waterston, R. H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520���562 (2002). [PMID: 12466850]
  21. Kazazian, H. H. Jr & Moran, J. V. Mobile DNA in health and disease. N. Engl. J. Med. 377, 361���370 (2017). [PMID: 28745987]
  22. Jachowicz, J. W. & Torres-Padilla, M. E. LINEs in mice: features, families, and potential roles in early development. Chromosoma 125, 29���39 (2016). [PMID: 25975894]
  23. Babushok, D. V. & Kazazian, H. H. Jr Progress in understanding the biology of the human mutagen LINE-1. Hum. Mutat. 28, 527���539 (2007). [PMID: 17309057]
  24. Goodier, J. L. & Kazazian, H. H. Jr Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell 135, 23���35 (2008). [PMID: 18854152]
  25. Martin, S. L. The ORF1 protein encoded by LINE-1: structure and function during L1 retrotransposition. J. Biomed. Biotechnol. 2006, 45621 (2006). [PMID: 16877816]
  26. Martin, S. L. Nucleic acid chaperone properties of ORF1p from the non-LTR retrotransposon, LINE-1. RNA Biol. 7, 706���711 (2010). [PMID: 21045547]
  27. Feng, Q., Moran, J. V., Kazazian, H. H. Jr. & Boeke, J. D. Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell 87, 905���916 (1996). [PMID: 8945517]
  28. Gasior, S. L., Wakeman, T. P., Xu, B. & Deininger, P. L. The human LINE-1 retrotransposon creates DNA double-strand breaks. J. Mol. Biol. 357, 1383���1393 (2006). [PMID: 16490214]
  29. Cost, G. J., Feng, Q., Jacquier, A. & Boeke, J. D. Human L1 element target-primed reverse transcription in vitro. EMBO J. 21, 5899���5910 (2002). [PMID: 12411507]
  30. Wallace, N. A., Belancio, V. P. & Deininger, P. L. L1 mobile element expression causes multiple types of toxicity. Gene 419, 75���81 (2008). [PMID: 18555620]
  31. Goodier, J. L. Restricting retrotransposons: a review. Mob. DNA 7, 16 (2016). [PMID: 27525044]
  32. Deniz O., Frost J. M. & Branco M. R. Regulation of transposable elements by DNA modifications. Nat. Rev. Genet. 20, 417���431 (2019).
  33. Saitou, M., Kagiwada, S. & Kurimoto, K. Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells. Development 139, 15���31 (2011). [DOI: 10.1242/dev.050849]
  34. Lees-Murdock, D. J., De Felici, M. & Walsh, C. P. Methylation dynamics of repetitive DNA elements in the mouse germ cell lineage. Genomics 82, 230���237 (2003). [PMID: 12837272]
  35. Lees-Murdock, D. J. & Walsh, C. P. DNA methylation reprogramming in the germ line. Epigenetics 3, 5���13 (2008). [PMID: 18259118]
  36. Aravin, A. A. & Bourc'his, D. Small RNA guides for de novo DNA methylation in mammalian germ cells. Genes Dev. 22, 970���975 (2008). [PMID: 18413711]
  37. Aravin, A. A. et al. A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Mol. Cell 31, 785���799 (2008). [PMID: 18922463]
  38. Castaneda, J., Genzor, P. & Bortvin, A. piRNAs, transposon silencing, and germline genome integrity. Mutat. Res. 714, 95���104 (2011). [PMID: 21600904]
  39. Di Giacomo, M. et al. Multiple epigenetic mechanisms and the piRNA pathway enforce LINE1 silencing during adult spermatogenesis. Mol. Cell 50, 601���608 (2013). [PMID: 23706823]
  40. Dai, L., Huang, Q. & Boeke, J. D. Effect of reverse transcriptase inhibitors on LINE-1 and Ty1 reverse transcriptase activities and on LINE-1 retrotransposition. BMC Biochem. 12, 18 (2011). [PMID: 21545744]
  41. Jones, R. B. et al. Nucleoside analogue reverse transcriptase inhibitors differentially inhibit human LINE-1 retrotransposition. PLoS ONE 3, e1547 (2008). [PMID: 18253495]
  42. Di Giacomo, M. et al. Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants. Proc. Natl Acad. Sci. USA 102, 737���742 (2005). [PMID: 15640358]
  43. Bolcun-Filas, E., Rinaldi, V. D., White, M. E. & Schimenti, J. C. Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway. Science 343, 533���536 (2014). [PMID: 24482479]
  44. Hirao, A. et al. Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner. Mol. Cell. Biol. 22, 6521���6532 (2002). [PMID: 12192050]
  45. Thomas, C. A. et al. Modeling of TREX1-dependent autoimmune disease using human stem cells highlights L1 accumulation as a source of neuroinflammation. Cell Stem Cell 21, 319���331 e318 (2017). [PMID: 28803918]
  46. De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73���78 (2019). [PMID: 30728521]
  47. Simon, M. et al. LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab. 29, 871���885 e875 (2019). [PMID: 30853213]
  48. Fan, X. et al. Single-cell reconstruction of follicular remodeling in the human adult ovary. Nat. Commun. 10, 3164 (2019). [PMID: 31320652]
  49. Mahadevaiah, S. K. et al. Recombinational DNA double-strand breaks in mice precede synapsis. Nat. Genet. 27, 271���276 (2001). [PMID: 11242108]
  50. Turner, J. M. et al. Silencing of unsynapsed meiotic chromosomes in the mouse. Nat. Genet. 37, 41���47 (2005). [PMID: 15580272]
  51. Kuramochi-Miyagawa, S. et al. Two mouse piwi-related genes: miwi and mili. Mech. Dev. 108, 121���133 (2001). [PMID: 11578866]
  52. Kuramochi-Miyagawa, S. et al. Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development 131, 839���849 (2004). [PMID: 14736746]
  53. Kloc, M., Bilinski, S. & Etkin, L. D. The Balbiani body and germ cell determinants: 150 years later. Curr. Top. Dev. Biol. 59, 1���36 (2004). [PMID: 14975245]
  54. Pepling, M. E., Wilhelm, J. E., O'Hara, A. L., Gephardt, G. W. & Spradling, A. C. Mouse oocytes within germ cell cysts and primordial follicles contain a Balbiani body. Proc. Natl Acad. Sci. USA 104, 187���192 (2007). [PMID: 17189423]
  55. Lei, L. & Spradling, A. C. Mouse oocytes differentiate through organelle enrichment from sister cyst germ cells. Science 352, 95���99 (2016). [PMID: 26917595]
  56. Hunter, N. Oocyte quality control: causes, mechanisms, and consequences. Cold Spring Harb. Symp. Quant. Biol. 82, 235���247 (2017). [PMID: 29743337]
  57. Flemr, M. et al. A retrotransposon-driven dicer isoform directs endogenous small interfering RNA production in mouse oocytes. Cell 155, 807���816 (2013). [PMID: 24209619]
  58. Wolf, G. et al. The KRAB zinc finger protein ZFP809 is required to initiate epigenetic silencing of endogenous retroviruses. Genes Dev. 29, 538���554 (2015). [PMID: 25737282]
  59. Yang, P., Wang, Y. & Macfarlan, T. S. The role of KRAB-ZFPs in transposable element repression and mammalian evolution. Trends Genet. 33, 871���881 (2017). [PMID: 28935117]
  60. Matova, N. & Cooley, L. Comparative aspects of animal oogenesis. Dev. Biol. 231, 291���320 (2001). [PMID: 11237461]
  61. Hikabe, O. et al. Reconstitution in vitro of the entire cycle of the mouse female germ line. Nature 539, 299���303 (2016). [PMID: 27750280]
  62. Malki, S., Tharp, M. E. & Bortvin, A. A whole-mount approach for accurate quantitative and spatial assessment of fetal oocyte dynamics in mice. Biol. Reprod. 93, 113 (2015). [PMID: 26423126]
  63. Tanaka, H. et al. A germ cell-specific nuclear antigen recognized by a monoclonal antibody raised against mouse testicular germ cells. Int. J. Androl. 20, 361���366 (1997). [PMID: 9568529]
  64. Wojtasz, L., Daniel, K. & Toth, A. Fluorescence activated cell sorting of live female germ cells and somatic cells of the mouse fetal gonad based on forward and side scattering. Cytometry Part A 75, 547���553 (2009). [DOI: 10.1002/cyto.a.20729]
  65. Trapnell, C., Pachter, L. & Salzberg, S. L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105���1111 (2009). [PMID: 19289445]
  66. Huang, D. W. et al. The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists. Genome Biol. 8, R183 (2007). [PMID: 17784955]
  67. Huang, D. W. et al. DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 35, W169���W175 (2007). [PMID: 17576678]
  68. Han, B. W., Wang, W., Zamore, P. D. & Weng, Z. piPipes: a set of pipelines for piRNA and transposon analysis via small RNA-seq, RNA-seq, degradome- and CAGE-seq, ChIP-seq and genomic DNA sequencing. Bioinformatics 31, 593���595 (2014).
  69. Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411���420 (2018). [PMID: 29608179]
  70. Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888���1902 e1821 (2019). [PMID: 31178118]

Grants

  1. F31 HD088053/NICHD NIH HHS
  2. R21 HD090514/NICHD NIH HHS

MeSH Term

Animals
Apoptosis
Argonaute Proteins
Checkpoint Kinase 2
DNA Damage
Female
Fertility
Fetus
Long Interspersed Nucleotide Elements
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutagenicity Tests
Oocytes
Oogenesis
Ovarian Reserve
RNA-Binding Proteins

Chemicals

Argonaute Proteins
ECAT11 protein, mouse
Piwil2 protein, mouse
RNA-Binding Proteins
Checkpoint Kinase 2
Chek2 protein, mouse
Journal Article Research Support, N.I.H., Extramural
Article has an altmetric score of 59

Word Cloud

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