Characterization and linkage mapping of an ENU-induced mutant mouse with defective spermatogenesis.

repro23 is an autosomal recessive mutation of the mouse generated by the N-ethyl-N-nitrosourea (ENU)-induced mutagenesis program at The Jackson Laboratory. The repro23/repro23 homozygous mouse shows male-specific infertility caused by defective spermatogenesis. In the present study, we investigated the testicular pathology of the affected mouse and performed linkage analysis to determine the chromosomal localization of the repro23 locus. Histological examination of the affected testis showed that the seminiferous epithelium of the repro23/repro23 mice contained spermatogonia and early stage spermatocytes, but no spermatids or spermatozoa. Immunohistochemical staining for Hsc70t, a spermatid specific protein, confirmed the absence of elongating spermatids. These findings indicated interruption of the spermatogenesis during meiosis in the repro23/repro23 mouse. By linkage analysis using 137 affected mice of F(2) progeny obtained from crosses between repro23/repro23 female and JF1/Ms (+/+) male mice, the repro23 locus was mapped to 2.2-Mb region of mouse chromosome 7. Although this region contains several potential candidate genes for the repro23 mutation, no gene already identified as a cause of defective spermatogenesis was in this region. Therefore, the gene responsible for the repro23 mutation is suggested to be a novel gene which plays an essential role in mammalian spermatogenesis.

[1]  M. Handel,et al.  Developmental control of sumoylation pathway proteins in mouse male germ cells. , 2008, Developmental biology.

[2]  K. Okuda,et al.  Leydig cell hyperplasia in an ENU-induced mutant mouse with germ cell depletion. , 2008, The Journal of reproduction and development.

[3]  T. Tsuji,et al.  A new ENU-induced mutant mouse with defective spermatogenesis caused by a nonsense mutation of the syntaxin 2/epimorphin (Stx2/Epim) gene. , 2008, The Journal of reproduction and development.

[4]  H. van Bokhoven,et al.  Homozygous mutation in SPATA16 is associated with male infertility in human globozoospermia. , 2007, American journal of human genetics.

[5]  N. Nakatsuji,et al.  Tdrd1/Mtr-1, a tudor-related gene, is essential for male germ-cell differentiation and nuage/germinal granule formation in mice , 2006, Proceedings of the National Academy of Sciences.

[6]  Mary Ann Handel,et al.  Mutagenesis as an unbiased approach to identify novel contraceptive targets , 2006, Molecular and Cellular Endocrinology.

[7]  P. Morris,et al.  Testicular expression of small ubiquitin-related modifier-1 (SUMO-1) supports multiple roles in spermatogenesis: silencing of sex chromosomes in spermatocytes, spermatid microtubule nucleation, and nuclear reshaping. , 2005, Developmental biology.

[8]  Y. Tanioka,et al.  Immunolocalization of steroidogenic enzymes P450scc, 3betaHSD, P450c17, and P450arom in Göttingen miniature pig testes. , 2005, The Journal of reproduction and development.

[9]  E. Kobayashi,et al.  Linkage mapping of the locus responsible for male pseudohermaphroditism (mp) on rat chromosome 7. , 2004, Experimental animals.

[10]  D. Escalier,et al.  Spermatid nuclear and sperm periaxonemal anomalies in the mouse Ube2b null mutant , 2003, Molecular reproduction and development.

[11]  Kazuhiro Kikuchi,et al.  Essential Role of Fkbp6 in Male Fertility and Homologous Chromosome Pairing in Meiosis , 2003, Science.

[12]  J. Hoeijmakers,et al.  Loss of HR6B Ubiquitin-Conjugating Activity Results in Damaged Synaptonemal Complex Structure and Increased Crossing-Over Frequency during the Male Meiotic Prophase , 2003, Molecular and Cellular Biology.

[13]  M. Matzuk,et al.  Genetic dissection of mammalian fertility pathways. , 2002, Nature cell biology.

[14]  P. Saunders,et al.  Human genetics and disease: Mouse models of male infertility , 2002, Nature Reviews Genetics.

[15]  N. Traficante,et al.  The Ubiquitin Ligase Component Siah1a Is Required for Completion of Meiosis I in Male Mice , 2002, Molecular and Cellular Biology.

[16]  R. C. Karn,et al.  FEMALE PREFERENCE FOR MALE SALIVA: IMPLICATIONS FOR SEXUAL ISOLATION OF MUS MUSCULUS SUBSPECIES , 2001, Evolution; international journal of organic evolution.

[17]  S. Narumiya,et al.  Ropporin, a sperm-specific binding protein of rhophilin, that is localized in the fibrous sheath of sperm flagella. , 2000, Journal of cell science.

[18]  R. Hay,et al.  Identification of the Enzyme Required for Activation of the Small Ubiquitin-like Protein SUMO-1* , 1999, The Journal of Biological Chemistry.

[19]  N. Tsunekawa,et al.  The Hsp70 homolog gene, Hsc70t, is expressed under translational control during mouse spermiogenesis , 1999, Molecular reproduction and development.

[20]  S. Narumiya,et al.  Rhophilin, a small GTPase Rho‐binding protein, is abundantly expressed in the mouse testis and localized in the principal piece of the sperm tail , 1999, FEBS letters.

[21]  A. Trounson,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1998 by The Endocrine Society Azoospermia Associated with a Mutation in the Ligand- Binding Domain of an Androgen Receptor Displaying Normal Ligand Binding, but Defective Trans , 2022 .

[22]  D. Dix,et al.  Targeted gene disruption of Hsp70-2 results in failed meiosis, germ cell apoptosis, and male infertility. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  S. Rozen,et al.  Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA–binding protein gene , 1995, Nature Genetics.

[24]  D. Bishop,et al.  Case-control study of whether subfertility in men is familial , 1994, BMJ.

[25]  I. Fattorini,et al.  Absent spermatogenesis despite early bilateral orchidopexy in 17-ketoreductase deficiency. , 1985 .