The reduction of oocytes and disruption of the meiotic prophase I in Fanconi anemia E-deficient mice

in Reproduction
Authors:
Huan YinDepartment of Obstetrics and Gynecology, Second Xiangya Hospital, Central South University, Changsha, China

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Suye SuyeDepartment of Obstetrics and Gynecology, Second Xiangya Hospital, Central South University, Changsha, China

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Zhixian ZhouDepartment of Obstetrics and Gynecology, Second Xiangya Hospital, Central South University, Changsha, China

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Haiyi CaiDepartment of Clinical Medicine, Harbin Medical University, Harbin, China

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Chun FuDepartment of Obstetrics and Gynecology, Second Xiangya Hospital, Central South University, Changsha, China

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https://orcid.org/0000-0001-6947-1159
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Correspondence should be addressed to C Fu; Email: fuchun0814@csu.edu.cn
DOI:
https://doi.org/10.1530/REP-21-0421
Volume/Issue:
Volume 164: Issue 3
Page Range:
71–82
Article Type:
Research Article
Online Publication Date:
14 Jul 2022
Copyright:
© Society for Reproduction and Fertility 2022
Restricted access

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In brief

Fanconi anemia results in subfertility and primary ovarian deficiency in females. This study reveals that disrupted meiosis in oocytes is one of the mechanisms involved.

Abstract

Fance is an important factor participating in the repair of DNA interstrand cross-links and its defect causes severe follicle depletion in female mice. To explore the underlying mechanisms, we investigated the effects of Fance on ovarian development in embryonic and newborn mice. We found that the number of oocytes was significantly decreased in Fance−/− mice as early as 13.5 days post coitum (dpc). The continuous decrease of oocytes in Fance−/− mice compared with the Fance+/+ mice led to the primordial follicles being almost exhausted at 2 days postpartum (dpp). The mitotic–meiotic transition occurred normally, but the meiotic progression was arrested in pachytene in Fance−/− oocytes. We detected the expressions of RAD51 (homologous recombination repair factor), 53BP1 (non-homologous end-joining repair factor), and γH2AX by immunostaining analysis and chromosome spreads. The expressions of 53BP1 were increased and RAD51 decreased significantly in Fance−/− oocytes compared with Fance+/+ oocytes. Also, the meiotic crossover indicated by MLH1 foci was significantly increased in Fance−/− oocytes. Oocyte proliferation and apoptosis were comparable between Fance−/− and Fance+/+ mice (P > 0.05). The aberrant high expression at 17.5 dpc and low expressions at 1 and 2 dpp indicated that the expression pattern of pluripotent marker OCT4 (POU5F1) was disordered in Fance−/− oocytes. These findings elucidate that Fance mutation leads to a progressive reduction of oocytes and disrupts the progression of meiotic prophase I but not the initiation. And, our study reveals that the potential mechanisms involve DNA damage repair, meiotic crossover, and pluripotency of oocytes.

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Print ISSN:
1470-1626
Online ISSN:
1741-7899

  • Adamo A, Collis SJ, Adelman CA, Silva N, Horejsi Z, Ward JD, Martinez-Perez E, Boulton SJ & La Volpe A 2010 Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. Molecular Cell 39 25–35. (https://doi.org/10.1016/j.molcel.2010.06.026)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Agoulnik AI, Lu B, Zhu Q, Truong C, Ty MT, Arango N, Chada KK & Bishop CE 2002 A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd. Human Molecular Genetics 11 3047–3053. (https://doi.org/10.1093/hmg/11.24.3047)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Alter BP, Frissora CL, Halpérin DS, Freedman MH, Chitkara U, Alvarez E, Lynch L, Adler-Brecher B & Auerbach AD 1991 Fanconi’s anaemia and pregnancy. British Journal of Haematology 77 410–418. (https://doi.org/10.1111/j.1365-2141.1991.tb08593.x)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Auerbach AD 2009 Fanconi anemia and its diagnosis. Mutation Research 668 4–10. (https://doi.org/10.1016/j.mrfmmm.2009.01.013)

  • Bakker ST, van de Vrugt HJ, Rooimans MA, Oostra AB, Steltenpool J, Delzenne-Goette E, van der Wal A, van der Valk M, Joenje H & te Riele H et al.2009 Fancm-deficient mice reveal unique features of Fanconi anemia complementation group M. Human Molecular Genetics 18 3484–3495. (https://doi.org/10.1093/hmg/ddp297)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Bakker ST, van de Vrugt HJ, Visser JA, Delzenne-Goette E, van der Wal A, Berns MA, van de Ven M, Oostra AB, de Vries S & Kramer P et al.2012 Fancf-deficient mice are prone to develop ovarian tumours. Journal of Pathology 226 28–39. (https://doi.org/10.1002/path.2992)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Bunting SF, Callén E, Wong N, Chen HT, Polato F, Gunn A, Bothmer A, Feldhahn N, Fernandez-Capetillo O & Cao L et al.2010 53BP1 inhibits homologous recombination in BRCA1-deficient cells by blocking resection of DNA breaks. Cell 141 243–254. (https://doi.org/10.1016/j.cell.2010.03.012)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Chen M, Tomkins DJ, Auerbach W, McKerlie C, Youssoufian H, Liu L, Gan O, Carreau M, Auerbach A & Groves T et al.1996 Inactivation of Fac in mice produces inducible chromosomal instability and reduced fertility reminiscent of Fanconi anaemia [letter]. Nature Genetics 12 448–451. (https://doi.org/10.1038/ng0496-448)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Cheng NC, van de Vrugt HJ, van der Valk MA, Oostra AB, Krimpenfort P, de Vries Y, Joenje H, Berns A & Arwert F 2000 Mice with a targeted disruption of the Fanconi anemia homolog Franca. Human Molecular Genetics 9 1805–1811. (https://doi.org/10.1093/hmg/9.12.1805)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Crossan GP, van der Weyden L, Rosado IV, Langevin F, Gaillard PHL & McIntyre RE Sanger Mouse Genetics Project, Gallagher F, Kettunen MI & Lewis DY et al.2011 Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. Nature Genetics 43 147–152. (https://doi.org/10.1038/ng.752)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Dai J, Voloshin O, Potapova S & Camerini-Otero RD 2017 Meiotic knockdown and complementation reveals essential role of RAD51 in mouse spermatogenesis. Cell Reports 18 1383–1394. (https://doi.org/10.1016/j.celrep.2017.01.024)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Fraison E, Crawford G, Casper G, Harris V & Ledger W 2019 Pregnancy following diagnosis of premature ovarian insufficiency: a systematic review. Reproductive Biomedicine Online 39 467–476. (https://doi.org/10.1016/j.rbmo.2019.04.019)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Fu C, Begum K & Overbeek PA 2016a Primary ovarian insufficiency induced by Fanconi anemia E mutation in a mouse model. PLoS ONE 11 1–13. (https://doi.org/10.1371/journal.pone.0144285)

    • Search Google Scholar
    • Export Citation

  • Fu C, Begum K, Jordan PW, He Y & Overbeek PA 2016b Dearth and delayed maturation of testicular germ cells in Fanconi anemia E mutant male mice. PLoS ONE 11 1–14. (https://doi.org/10.1371/journal.pone.0159800)

    • Search Google Scholar
    • Export Citation

  • Giacomo MD, Barchi M, Baudat F, Edelmann W, Keeney S & Jasin M 2005 Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants. PNAS 102 737–7 42. (https://doi.org/10.1073/pnas.0406212102)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Hartford SA, Chittela R, Ding X, Vyas A, Martin B, Burkett S, Haines DC, Southon E, Tessarollo L & Sharan SK 2016 Interaction with PALB2 is essential for maintenance of genomic integrity by BRCA2. PLoS Genetics 12 e1006236. (https://doi.org/10.1371/journal.pgen.1006236)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Holloway JK, Mohan S, Balmus G, Sun X, Modzelewski A, Borst PL, Freire R, Weiss RS & Cohen PE 2011 Mammalian BTBD12 (SLX4) protects against genomic instability during mammalian spermatogenesis. PLoS Genetics 7 e1002094. (https://doi.org/10.1371/journal.pgen.1002094)

    • Search Google Scholar
    • Export Citation

  • Houghtaling S, Timmers C, Noll M, Finegold MJ, Jones SN, Meyn MS & Grompe M 2003 Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice. Genes and Development 17 2021–2035. (https://doi.org/10.1101/gad.1103403)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Jiao X, Ke H, Qin Y & Chen ZJ 2018 Molecular genetics of premature ovarian insufficiency. Trends in Endocrinology and Metabolism 29 795–807. (https://doi.org/10.1016/j.tem.2018.07.002)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Jung D, Xiong J, Ye M, Qin X, Li L, Cheng S, Luo M, Peng J, Dong J & Tang F et al.2017 In vitro differentiation of human embryonic stem cells into ovarian follicle-like cells. Nature Communications 8 15680. (https://doi.org/10.1038/ncomms15680)

    • Search Google Scholar
    • Export Citation

  • Knies K, Inano S, Ramírez MJ, Ishiai M, Surrallés J, Takata M & Schindler D 2017 Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia. Journal of Clinical Investigation 127 3013–3027. (https://doi.org/10.1172/JCI92069)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Koomen M, Cheng NC, van de Vrugt HJ, Godthelp BC, van der Valk MA, Oostra AB, Zdzienicka MZ, Joenje H & Arwert F 2002 Reduced fertility and hypersensitivity to Mitomycin C characterize Francg/Xrcc9 null mice. Human Molecular Genetics 11 273–281. (https://doi.org/10.1093/hmg/11.3.273)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Kuznetsov S, Pellegrini M, Shuda K, Fernandez-Capetillo O, Liu Y, Martin BK, Burkett S, Southon E, Pati D & Tessarollo L et al.2007 RAD51C deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females. Journal of Cell Biology 176 581–592. (https://doi.org/10.1083/jcb.200608130)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Luo Y, Hartford SA, Zeng R, Southard TL, Shima N & Schimenti JC 2014 Hypersensitivity of primordial germ cells to compromised replication-associated DNA repair involves ATM-p53-p21 signaling. PLoS Genetics 10 e1004471. (https://doi.org/10.1371/journal.pgen.1004471)

    • Search Google Scholar
    • Export Citation

  • Moldovan GL & D’Andrea AD 2009 How the Fanconi anemia pathway guards the genome. Annual Review of Genetics 43 223–249. (https://doi.org/10.1146/annurev-genet-102108-134222)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Myers M, Morgan FH, Liew SH, Zerafa N, Gamage TU, Sarraj M, Cook M, Kapic I, Sutherland A & Scott CL et al.2014 PUMA regulates germ cell loss and primordial follicle endowment in mice. Reproduction 148 211–219. (https://doi.org/10.1530/REP-13-0666)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Nadler JJ & Braun RE 2000 Fanconi anemia complementation group C is required for proliferation of murine primordial germ cells. Genesis 27 117–123. (https://doi.org/10.1002/1526-968x(200007)27:3<117::aid-gene40>3.0.co;2-7)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Niraj J, Färkkilä A & D’Andrea AD 2019 The Fanconi anemia pathway in cancer. Annual Review of Cancer Biology 3 457–478. (https://doi.org/10.1146/annurev-cancerbio-030617-050422)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Pace P, Johnson M, Tan WM, Mosedale G, Sng C, Hoatlin M, de Winter J, Joenje H, Gergely F & Patel KJ 2002 FANCE: the link between Fanconi anaemia complex assembly and activity. EMBO Journal 21 3414–3423. (https://doi.org/10.1093/emboj/cdf355)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Pesce M, Wang X, Wolgemuth DJ & Schöler H 1998 Differential expression of the Oct-4 transcription factor during mouse germ cell differentiation. Mechanisms of Development 71 89–98. (https://doi.org/10.1016/s0925-4773(9800002-1)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Qin Y, Jiao X, Simpson JL & Chen ZJ 2015 Genetics of primary ovarian insufficiency: new developments and opportunities. Human Reproduction Update 21 787–808. (https://doi.org/10.1093/humupd/dmv036)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Sharan SK, Pyle A, Coppola V, Babus J, Swaminathan S, Benedict J, Swing D, Martin BK, Tessarollo L & Evans JP et al.2004 BRCA2 deficiency in mice leads to meiotic impairment and infertility. Development 131 131–142. (https://doi.org/10.1242/dev.00888)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Sun X, Brieño-Enríquez MA, Cornelius A, Modzelewski AJ, Maley TT, Campbell-Peterson KM, Holloway JK & Cohen PE 2016 FancJ (Brip1) loss-of-function allele results in spermatogonial cell depletion during embryogenesis and altered processing of crossover sites during meiotic prophase I in mice. Chromosoma 125 237–252. (https://doi.org/10.1007/s00412-015-0549-2)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Tan W & Deans AJ 2017 A defined role for multiple fanconi anemia gene products in DNA-damage-associated ubiquitination. Experimental Hematology 50 27–32. (https://doi.org/10.1016/j.exphem.2017.03.001)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Tsui V & Crismani W 2019 The fanconi anemia pathway and fertility. Trends in Genetics 35 199–214. (https://doi.org/10.1016/j.tig.2018.12.007)

  • Tu Z, Mu X, Chen X, Geng Y, Zhang Y, Li Q, Gao R, Liu T, Wang Y & He J 2019 Dibutyl phthalate exposure disrupts the progression of meiotic prophase I by interfering with homologous recombination in fetal mouse oocytes. Environmental Pollution 252 388–398. (https://doi.org/10.1016/j.envpol.2019.05.107)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Watanabe N, Mii S, Asai N, Asai M, Niimi K, Ushida K, Kato T, Enomoto A, Ishii H & Takahashi M et al.2013 The REV7 subunit of DNA polymerase ζ is essential for primordial germ cell maintenance in the mouse. Journal of Biological Chemistry 288 10459–10471. (https://doi.org/10.1074/jbc.M112.421966)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Weinberg-Shukron A, Rachmiel M, Renbaum P, Gulsuner S, Walsh T, Lobel O, Dreifuss A, Ben-Moshe A, Zeligson S & Segel R et al.2018 Essential role of BRCA2 in ovarian development and function. New England Journal of Medicine 379 1042–1049. (https://doi.org/10.1056/NEJMoa1800024)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Wesevich V, Kellen AN & Pal L 2020 Recent advances in understanding primary ovarian insufficiency. F1000Research 9 1–13. (https://doi.org/10.12688/f1000research.26423.1)

    • Search Google Scholar
    • Export Citation

  • Whitney MA, Royle G, Low MJ, Kelly MA, Axthelm MK, Reifsteck C, Olson S, Braun RE, Heinrich MC & Rathbun RK et al.1996 Germ cell defects and hematopoietic hypersensitivity to γ-interferon in mice with a targeted disruption of the fanconi anemia C gene. Blood 88 49–58. (https://doi.org/10.1182/blood.V88.1.49.49)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Wong JC, Alon N, Mckerlie C, Huang JR, Meyn MS & Buchwald M 2003 Targeted disruption of exons 1 to 6 of the fanconi anemia group a gene leads to growth retardation, strain-specific microphthalmia, meiotic defects and primordial germ cell hypoplasia. Human Molecular Genetics 12 2063–2076. (https://doi.org/10.1093/hmg/ddg219)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Xu X, Aprelikova O, Moens P, Deng CX & Furth PA 2003 Impaired meiotic DNA-damage repair and lack of crossing-over during spermatogenesis in BRCA1 full-length isoform deficient mice. Development 130 2001–2012. (https://doi.org/10.1242/dev.00410)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Yang Y, Kuang Y, Montes De Oca R, Hays T, Moreau L, Lu N, Seed B & D’Andrea AD 2001 Targeted disruption of the murine fanconi anemia gene, Fancg/Xrcc9. Blood 98 3435–3440. (https://doi.org/10.1182/blood.v98.12.3435)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Yang Y, Guo J, Dai L, Zhu Y, Hu H, Tan L, Chen W, Liang D, He J & Tu M et al.2018 XRCC2 mutation causes meiotic arrest, azoospermia and infertility. Journal of Medical Genetics 55 628–636. (https://doi.org/10.1136/jmedgenet-2017-105145)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Yang X, Zhang X, Jiao J, Zhang F, Pan Y, Wang Q, Chen Q, Cai B, Tang S & Zhou Z et al.2019 Rare variants in FANCA induce premature ovarian insufficiency. Human Genetics 138 1227–1236. (https://doi.org/10.1007/s00439-019-02059-9)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Yin H, Ma H, Hussain S, Zhang H, Xie X, Jiang L, Jiang X, Iqbal F, Bukhari I & Jiang H et al.2019 A homozygous FANCM frameshift pathogenic variant causes male infertility. Genetics in Medicine 21 62–70. (https://doi.org/10.1038/s41436-018-0015-7)

    • Crossref
    • Search Google Scholar
    • Export Citation

  • Zimmermann M & de Lange T 2014 53BP1: pro choice in DNA repair. Trends in Cell Biology 24 108–117. (https://doi.org/10.1016/j.tcb.2013.09.003)