Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice

Aneuploidy, the most common chromosomal abnormality at birth and the main ascertained cause of pregnancy loss in humans, originates primarily from chromosome segregation errors during oogenesis. Here, we report that heterozygosity for a mutation in the mitotic checkpoint kinase gene, Bub1, induces aneuploidy in female germ cells of mice and that the effect increases with advancing maternal age. Analysis of Bub1 heterozygous oocytes showed that aneuploidy occurred primarily during the first meiotic division and involved premature sister chromatid separation. Furthermore, aneuploidy was inherited in zygotes and resulted in the loss of embryos after implantation. The incidence of aneuploidy in zygotes was sufficient to explain the reduced litter size in matings with Bub1 heterozygous females. No effects were seen in germ cells from heterozygous males. These findings show that Bub1 dysfunction is linked to inherited aneuploidy in female germ cells and may contribute to the maternal age-related increase in aneuploidy and pregnancy loss.

[1]  Stephen S. Taylor,et al.  Regulation of APC/C Activity in Oocytes by a Bub1-Dependent Spindle Assembly Checkpoint , 2009, Current Biology.

[2]  Martin M Matzuk,et al.  The biology of infertility: research advances and clinical challenges , 2008, Nature Medicine.

[3]  J. B. Mailhes.  Faulty spindle checkpoint and cohesion protein activities predispose oocytes to premature chromosome separation and aneuploidy , 2008, Environmental and molecular mutagenesis.

[4]  Luis E. Vázquez-Quiñones,et al.  Shugoshin-2 is essential for the completion of meiosis but not for mitotic cell division in mice. , 2008, Genes & development.

[5]  M. Kirsch‐Volders,et al.  Spindle formation, chromosome segregation and the spindle checkpoint in mammalian oocytes and susceptibility to meiotic error. , 2008, Mutation research.

[6]  P. Sorger,et al.  Changing Mad2 Levels Affects Chromosome Segregation and Spindle Assembly Checkpoint Control in Female Mouse Meiosis I , 2007, PloS one.

[7]  D. Baker,et al.  Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis , 2007, The Journal of cell biology.

[8]  Terry Hassold,et al.  The origin of human aneuploidy: where we have been, where we are going. , 2007, Human molecular genetics.

[9]  Stephen S. Taylor,et al.  Bub1 maintains centromeric cohesion by activation of the spindle checkpoint. , 2007, Developmental cell.

[10]  M. Herbert,et al.  Bi-orientation of achiasmatic chromosomes in meiosis I oocytes contributes to aneuploidy in mice , 2007, Nature Genetics.

[11]  E. Salmon,et al.  The spindle-assembly checkpoint in space and time , 2007, Nature Reviews Molecular Cell Biology.

[12]  S. West,et al.  RAD51C deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females , 2007, The Journal of cell biology.

[13]  K. Hardwick,et al.  The spindle checkpoint , 2006, Journal of Cell Science.

[14]  J. V. van Deursen,et al.  Differential mitotic checkpoint protein requirements in somatic and germ cells. , 2006, Biochemical Society transactions.

[15]  J. Ellenberg,et al.  Resolution of Chiasmata in Oocytes Requires Separase-Mediated Proteolysis , 2006, Cell.

[16]  Masao Nagata,et al.  Inadequate histone deacetylation during oocyte meiosis causes aneuploidy and embryo death in mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Karl Mechtler,et al.  Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I , 2006, Nature.

[18]  F. Vialard,et al.  Evidence of a high proportion of premature unbalanced separation of sister chromatids in the first polar bodies of women of advanced age. , 2006, Human reproduction.

[19]  E. Revenkova,et al.  SMC1β-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction , 2005, Nature Genetics.

[20]  P. Sorger,et al.  A dual role for Bub1 in the spindle checkpoint and chromosome congression , 2005, The EMBO journal.

[21]  T. Kitajima,et al.  Human Bub1 Defines the Persistent Cohesion Site along the Mitotic Chromosome by Affecting Shugoshin Localization , 2005, Current Biology.

[22]  A. Murdoch,et al.  Mad2 prevents aneuploidy and premature proteolysis of cyclin B and securin during meiosis I in mouse oocytes. , 2005, Genes & development.

[23]  S. Geley,et al.  The spindle assembly checkpoint is not essential for CSF arrest of mouse oocytes , 2004, The Journal of cell biology.

[24]  Hongtao Yu,et al.  Human Bub1 protects centromeric sister-chromatid cohesion through Shugoshin during mitosis , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[25]  K. Wigglesworth,et al.  ATRX, a member of the SNF2 family of helicase/ATPases, is required for chromosome alignment and meiotic spindle organization in metaphase II stage mouse oocytes. , 2004, Developmental biology.

[26]  R. Kumar,et al.  BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice , 2004, Nature Genetics.

[27]  E. Revenkova,et al.  Cohesin SMC1β is required for meiotic chromosome dynamics, sister chromatid cohesion and DNA recombination , 2004, Nature Cell Biology.

[28]  Stephen S. Taylor,et al.  Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression , 2004, Journal of Cell Science.

[29]  T. Kitajima,et al.  The conserved kinetochore protein shugoshin protects centromeric cohesion during meiosis , 2004, Nature.

[30]  A. Murdoch,et al.  Homologue disjunction in mouse oocytes requires proteolysis of securin and cyclin B1 , 2003, Nature Cell Biology.

[31]  S. Brunet,et al.  Functionality of the spindle checkpoint during the first meiotic division of mammalian oocytes. , 2003, Reproduction.

[32]  B. Maro,et al.  Metaphase I Arrest upon Activation of the Mad2-Dependent Spindle Checkpoint in Mouse Oocytes , 2003, Current Biology.

[33]  K. Sullivan,et al.  Centromeres and Kinetochores From Epigenetics to Mitotic Checkpoint Signaling , 2003, Cell.

[34]  Hongtao Yu,et al.  Regulation of APC-Cdc20 by the spindle checkpoint. , 2002, Current opinion in cell biology.

[35]  P. Hunt,et al.  Sex Matters in Meiosis , 2002, Science.

[36]  Li Yuan,et al.  Female Germ Cell Aneuploidy and Embryo Death in Mice Lacking the Meiosis-Specific Protein SCP3 , 2002, Science.

[37]  Emma Lees,et al.  Identification of an Overlapping Binding Domain on Cdc20 for Mad2 and Anaphase-Promoting Complex: Model for Spindle Checkpoint Regulation , 2001, Molecular and Cellular Biology.

[38]  J. Javerzat,et al.  Fission yeast Bub1 is essential in setting up the meiotic pattern of chromosome segregation , 2001, Nature Cell Biology.

[39]  P. Hunt,et al.  To err (meiotically) is human: the genesis of human aneuploidy , 2001, Nature Reviews Genetics.

[40]  K. Choo,et al.  Bub3 gene disruption in mice reveals essential mitotic spindle checkpoint function during early embryogenesis. , 2000, Genes & development.

[41]  N. Steuerwald,et al.  Association between spindle assembly checkpoint expression and maternal age in human oocytes. , 2000, Molecular human reproduction.

[42]  J. Eriksson,et al.  Differences in spindle association of the mitotic checkpoint protein Mad2 in mammalian spermatogenesis and oogenesis. , 2000, Developmental biology.

[43]  P. Sorger,et al.  Chromosome Missegregation and Apoptosis in Mice Lacking the Mitotic Checkpoint Protein Mad2 , 2000, Cell.

[44]  S. O’Gorman,et al.  Protamine-Cre recombinase transgenes efficiently recombine target sequences in the male germ line of mice, but not in embryonic stem cells. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[45]  F. Spencer,et al.  Mammalian BUB1 protein kinases: map positions and in vivo expression. , 1997, Genomics.

[46]  Stephen S. Taylor,et al.  Kinetochore Localization of Murine Bub1 Is Required for Normal Mitotic Timing and Checkpoint Response to Spindle Damage , 1997, Cell.

[47]  J. B. Mailhes,et al.  Cytogenetic technique for mouse metaphase II oocytes. , 1987, Gamete research.

[48]  T. Kitajima,et al.  Unified mode of centromeric protection by shugoshin in mammalian oocytes and somatic cells , 2008, Nature Cell Biology.

[49]  Conrad C. Huang,et al.  BayGenomics: a resource of insertional mutations in mouse embryonic stem cells , 2003, Nucleic Acids Res..

[50]  M. Hoyt,et al.  Genetic analysis of the mitotic spindle. , 1996, Annual review of genetics.

[51]  R. Donahue.  Cytogenetic analysis of the first cleavage division in mouse embryos (fertilization-pronuclei-T163H translocation). , 1972, Proceedings of the National Academy of Sciences of the United States of America.

[52]  C. E. Ford,et al.  AN AIR-DRYING METHOD FOR MEIOTIC PREPARATIONS FROM MAMMALIAN TESTES. , 1964, Cytogenetics.