RESUMO
We generated mice lacking Cks2, one of two mammalian homologs of the yeast Cdk1-binding proteins, Suc1 and Cks1, and found them to be viable but sterile in both sexes. Sterility is due to failure of both male and female germ cells to progress past the first meiotic metaphase. The chromosomal events up through the end of prophase I are normal in both CKS2-/- males and females, suggesting that the phenotype is due directly to failure to enter anaphase and not a consequence of a checkpoint-mediated metaphase I arrest.
Assuntos
Anáfase , Quinases relacionadas a CDC2 e CDC28 , Proteína Quinase CDC28 de Saccharomyces cerevisiae/fisiologia , Meiose , Metáfase , Oócitos/fisiologia , Espermatócitos/fisiologia , Animais , Apoptose , Proteína Quinase CDC28 de Saccharomyces cerevisiae/genética , Proteínas de Ciclo Celular , Segregação de Cromossomos , Ciclina A/metabolismo , Ciclina B/metabolismo , Epididimo/citologia , Epididimo/fisiologia , Feminino , Marcação de Genes , Hibridização In Situ , Infertilidade Feminina/fisiopatologia , Infertilidade Masculina/fisiopatologia , Masculino , Camundongos , Mutação , Ovário/citologia , Ovário/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Recombinação Genética , Espermatogênese , Testículo/citologia , Testículo/fisiologiaRESUMO
In a wide variety of animal species, oocyte maturation is arrested temporarily at prophase of meiosis I (ref. 1). Resumption of meiosis requires activation of cyclin-dependent kinase-1 (CDK1, p34cdc2), one component of maturation-promoting factor (MPF). The dual specificity phosphatases Cdc25a, Cdc25b and Cdc25c are activators of cyclin-dependent kinases; consequently, they are postulated to regulate cell-cycle progression in meiosis and mitosis as well as the DNA-damage response. We generated Cdc25b-deficient (Cdc25b-/-) mice and found that they are viable. As compared with wildtype cells, fibroblasts from Cdc25b-/- mice grew vigorously in culture and arrested normally in response to DNA damage. Female Cdc25b-/- mice were sterile, and Cdc25b-/- oocytes remained arrested at prophase with low MPF activity. Microinjection of wildtype Cdc25b mRNA into Cdc25b-/- oocytes caused activation of MPF and resumption of meiosis. Thus, Cdc25b-/- female mice are sterile because of permanent meiotic arrest resulting from the inability to activate MPF. Cdc25b is therefore essential for meiotic resumption in female mice. Mice lacking Cdc25b provide the first genetic model for studying the mechanisms regulating prophase arrest in vertebrates.
