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Analysis of factors decreasing testis weight in MRL mice

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Abstract

MRL/MpJ (MRL) mouse testes have several unique characteristics, including the appearance of oocytes, the occurrence of metaphase-specific apoptosis of meiotic spermatocytes, and the presence of heat-shock-resistant spermatocytes. In the present study we used chromosomal mapping to determine the genomic background associated with small testis size in MRL mice. We prepared and analyzed C57BL/6-based congenic mice carrying MRL mouse loci. Quantitative trait loci (QTL) analysis revealed susceptibility loci for small testis size at 100 cM on chromosome (Chr) 1 and at around 80 cM on Chr 2. Analysis with B6.MRLc1 and B6.MRLc2 congenic mice and double-congenic mice confirmed the QTL data and showed that low testis weight in MRL mice was caused by germ cell apoptosis. Through histological examinations we found that B6.MRLc1 and B6.MRLc2 mice showed stage-specific apoptosis in their testes, the former at metaphase stage XII and the later at pachytene stage IV. Metaphase-specific apoptosis of spermatocytes occurs due to mutation of the exonuclease 1 (Exo1) gene located at 100 cM on Chr 1. Thus, the mutation of the Exo1 gene is also responsible for low testis weight caused by metaphase-specific apoptosis. In conclusion, testis weight is reduced in MRL mice due to apoptosis of germ cells caused by mutations in loci on Chrs 1 and 2.

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References

  • Baidat F, Manova K, Yuen JP, Jasin M, Keeney S (2000) Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Mol Cell 6:989–998

    Article  Google Scholar 

  • Barchi M, Roig I, Di Giacomo M, de Rooij DG, Keeney S et al (2008) ATM promotes the obligate XY crossover and both crossover control and chromosome axis integrity on autosomes. PLoS Genet 4:e1000076

    Article  PubMed  Google Scholar 

  • Carrell DT, De Jonge C, Lamb DJ (2006) The genetics of male infertility: a field of study whose time is now. Arch Androl 52:269–274

    Article  CAS  PubMed  Google Scholar 

  • Clark LD, Clark RK, Heber-Katz E (1998) A new murine model for mammalian wound repair and regeneration. Clin Immunol Immunopathol 88:35–45

    Article  CAS  PubMed  Google Scholar 

  • Cohen PE, Pollack SE, Pollard JW (2006) Genetic analysis of chromosome pairing, recombination, and cell cycle control during first meiotic prophase in mammals. Endocr Rev 27:398–426

    Article  CAS  PubMed  Google Scholar 

  • Dohle GR, Smit M, Weber RF (2003) Androgens and male fertility. World J Urol 21:341–345

    Article  CAS  PubMed  Google Scholar 

  • Eaker S, Pyle A, Cobb J, Handel MA (2001) Evidence for meiotic spindle checkpoint from analysis of spermatocytes from Robertsonian-chromosome heterozygous mice. J Cell Sci 114:2953–2965

    CAS  PubMed  Google Scholar 

  • Eaker S, Cobb J, Pyle A, Handel MA (2002) Meiotic prophase abnormalities and metaphase cell death in MLH1-deficient mouse spermatocytes: insights into regulation of spermatogenic progress. Dev Biol 249:85–95

    Article  CAS  PubMed  Google Scholar 

  • Edelmann W, Cohen PE, Kneitz B, Winand N, Lia M et al (1999) Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nat Genet 21:123–127

    Article  CAS  PubMed  Google Scholar 

  • Hamer G, Novok I, Kouznetsova A, Höög C (2008) Disruption of pairing and synapsis of chromosomes causes stage-specific apoptosis of male meiotic cells. Theriogenology 69:333–339

    Article  CAS  PubMed  Google Scholar 

  • Hoffmann ER, Borts RH (2004) Meiotic recombination intermediates and mismatch repair proteins. Cytogenet Genome Res 107:232–248

    Article  CAS  PubMed  Google Scholar 

  • Ichii O, Konno A, Sasaki N, Endoh D, Hashimoto Y et al (2008) Autoimmune glomerulonephritis induced in congenic mouse strain carrying telomeric region of chromosome 1 derived from MRL/MpJ. Histol Histopathol 23:411–422

    CAS  PubMed  Google Scholar 

  • Kon Y (2005) Morphogenetic investigation of metaphase-specific cell death in meiotic spermatocytes in mice. Anat Sci Int 80:141–152

    Article  PubMed  Google Scholar 

  • Kon Y, Endoh D (2000) Morphological study of metaphase-specific apoptosis in MRL mouse testis. Anat Histol Embryol 29:313–319

    Article  CAS  PubMed  Google Scholar 

  • Kon Y, Endoh D (2001) Heat-shock resistance in experimental cryptorchid testis of mice. Mol Reprod Dev 58:216–222

    Article  CAS  PubMed  Google Scholar 

  • Kon Y, Horikoshi H, Endoh D (1999) Metaphase-specific cell death in meiotic spermatocytes in mice. Cell Tissue Res 296:359–369

    Article  CAS  PubMed  Google Scholar 

  • Leblond CP, Clermont Y (1952) Spermiogenesis of rat, mouse, hamster and guinea pig as revealed by the “periodic acid–fuchsin sulfurous acid” technique. Am J Anat 90:167–215

    Article  CAS  PubMed  Google Scholar 

  • Leferovich JM, Bedelbaeva K, Samulewicz S, Zhang XM, Zwas D et al (2001) Heart regeneration in adult MRL mice. Proc Natl Acad Sci USA 98:9830–9835

    Article  CAS  PubMed  Google Scholar 

  • Mahadevaiah SK, Bourc’his D, de Rooij DG, Bestor TH, Turner JM et al (2008) Extensive meiotic asynapsis in mice antagonizes meiotic silencing of unsynapsed chromatin and consequently disrupts meiotic sex chromosome inactivation. J Cell Biol 182:263–276

    Article  CAS  PubMed  Google Scholar 

  • Manly KF, Cudmore RH Jr, Meer JM (2001) Map Manager QTX, cross-platform software for genetic mapping. Mamm Genome 12:930–932

    Article  CAS  PubMed  Google Scholar 

  • Martin RH, Green J, Ko E, Barclay L, Rademaker AW (2000) Analysis of aneuploidy frequencies in sperm from patients with hereditary nonpolyposis colon cancer and an hMSH2 mutation. Am J Hum Genet 66:1149–1152

    Article  CAS  PubMed  Google Scholar 

  • Merico V, de Barboza GD, Vasco C, Ponce R, Rodriguez V et al (2008) A mitochondrial mechanism is involved in apoptosis of Robertsonian mouse male germ cells. Reproduction 135:797–804

    Article  CAS  PubMed  Google Scholar 

  • Murphy ED (1981) Lymphoproliferation (lpr) and other single-locus models for murine lupus. In: Gershwin ME, Merchant B (eds) Immunologic defects in laboratory animals. Plenum Press, New York, pp 143–173

    Google Scholar 

  • Namiki Y, Endoh D, Kon Y (2003) Genetic mutation associated with meiotic metaphase-specific apoptosis in MRL/MpJ mice. Mol Reprod Dev 64:179–188

    Article  CAS  PubMed  Google Scholar 

  • Namiki Y, Kon Y, Sasaki N, Agui T, Endoh D (2004) Exon skipping of exonuclease 1 in MRL/MpJ mice is caused by a nucleotide substitution of the branchpoint sequence in intron eight. Jpn J Vet Res 52:125–134

    PubMed  Google Scholar 

  • Namiki Y, Kon Y, Kazusa K, Asano A, Sasaki N et al (2005) Quantitative trait loci analysis of heat stress resistance of spermatocytes in the MRL/MpJ mouse. Mamm Genome 16:96–102

    Article  CAS  PubMed  Google Scholar 

  • Oakberg EF (1956) Duration of spermatogenesis in the mouse and timing of stages of the cycle in the seminiferous epithelium. Am J Anat 99:507–519

    Article  CAS  PubMed  Google Scholar 

  • Otsuka S, Konno A, Hashimoto Y, Sasaki N, Endoh D et al (2008a) Oocytes in newborn MRL mouse testes. Biol Reprod 79:9–16

    Article  CAS  PubMed  Google Scholar 

  • Otsuka S, Konno A, Hashimoto Y, Sasaki N, Endoh D et al (2008b) Polymorphism in MRL and AKR mice Sry: a candidate gene for the appearance of testicular oocyte. Jpn J Vet Res 56:129–138

    PubMed  Google Scholar 

  • Roeder GS, Bailis JM (2000) The pachytene checkpoint. Trends Genet 16:395–403

    Article  CAS  PubMed  Google Scholar 

  • Romanienko P, Camerini-Otero RD (2000) The mouse Spo11 gene is required for meiotic chromosome synapsis. Mol Cell 6:975–987

    Article  CAS  PubMed  Google Scholar 

  • Russell LD, Ettlin RA, Sinha-Hikim AP, Clegg ED (1990) Histological and histopathological evaluation of the testis. Cache River Press, Clearwater, FL

    Google Scholar 

  • Sairam MR, Krishnamurthy H (2001) The role of follicle-stimulating hormone in spermatogenesis: lessons from knockout animal models. Arch Med Res 32:601–608

    Article  CAS  PubMed  Google Scholar 

  • Schmutte C, Marinescu RC, Sadoff MM, Guerrette S, Overhauser J et al (1998) Human exonuclease I interacts with the mismatch repair protein hMSH2. Cancer Res 58:4537–4542

    CAS  PubMed  Google Scholar 

  • Schmutte C, Sadoff MM, Shim KS, Acharya S, Fishel R (2001) The interaction of DNA mismatch repair proteins with human exonuclease I. J Biol Chem 276:33011–33018

    Article  CAS  PubMed  Google Scholar 

  • Selva DM, Tirado OM, Toràn N, Suárez-Quian CA, Reventós J et al (2000) Meiotic arrest and germ cell apoptosis in androgen-binding protein transgenic mice. Endocrinology 141:1168–1177

    Article  CAS  PubMed  Google Scholar 

  • Theofilopoulos AN, Dixon FJ (1985) Murine models of systemic lupus erythematosus. Adv Immunol 37:269–390

    Article  CAS  PubMed  Google Scholar 

  • Toshimori K, Ito C, Maekawa M, Toyama Y, Suzuki-Toyota F et al (2004) Impairment of spermatogenesis leading to infertility. Anat Sci Int 79:101–111

    Article  CAS  PubMed  Google Scholar 

  • Tourtellotte WG, Nagarajan R, Auyeung A, Mueller C, Milbrandt J (1999) Infertility associated with incomplete spermatogenetic arrest and oliglzoospermia in Egf4-deficient mice. Development 126:5061–5071

    CAS  PubMed  Google Scholar 

  • Wang WH, Sun QY (2006) Meiotic spindle, spindle checkpoint and embryonic aneuploidy. Front Biosci 11:620–636

    Article  CAS  PubMed  Google Scholar 

  • Wei K, Clark AB, Wong E, Kane MF, Mazur DJ et al (2003) Inactivation of exonuclease 1 in mice results in DNA mismatch repair defects, increased cancer susceptibility, and male and female sterility. Genes Dev 17:603–614

    Article  CAS  PubMed  Google Scholar 

  • Xu Y, Ashley T, Brainerd EE, Bronson RT, Meyn MS et al (1996) Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev 10:2411–2422

    Article  CAS  PubMed  Google Scholar 

  • Yoshida K, Kondoh G, Matsuda Y, Habu T, Nishimune Y et al (1998) The mouse RecA-like gene Dmc1 is required for homologous chromosome synapsis during meiosis. Mol Cell 1:707–718

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (16380194, 19380162, and 19658106).

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Authors and Affiliations

  1. Office for Faculty Development and Teaching Enriched Veterinary Medicine, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan

    Saori Otsuka & Yoshiharu Hashimoto

  2. Laboratory of Anatomy, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18 Nishi 9, Kita-ku, Sapporo, 060-0818, Japan

    Saori Otsuka, Osamu Ichii, Yoshiharu Hashimoto & Yasuhiro Kon

  3. Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

    Yuka Namiki

  4. Laboratory of Experimental Animal Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan

    Nobuya Sasaki

  5. Department of Veterinary Radiology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, 069-8501, Japan

    Daiji Endoh

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  1. Saori Otsuka
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  2. Yuka Namiki
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  3. Osamu Ichii
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  7. Yasuhiro Kon
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Correspondence to Yasuhiro Kon.

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Otsuka, S., Namiki, Y., Ichii, O. et al. Analysis of factors decreasing testis weight in MRL mice. Mamm Genome 21, 153–161 (2010). https://doi.org/10.1007/s00335-010-9251-0

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  • DOI: https://doi.org/10.1007/s00335-010-9251-0

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