Cdc20 Is Critical for Meiosis I and Fertility of Female Mice 英文参考文献.docVIP

Cdc20IsCriticalforMeiosisIandFertilityofFemaleMice FangJin1,MasakazuHamada2,LiviuMalureanu1,KarthikB.Jeganathan1,WeiZhou1,DeanE.Morbeck3, JanM.vanDeursen1,2 * 1DepartmentofPediatricandAdolescentMedicine,MayoClinicCollegeofMedicine,Rochester,Minnesota,UnitedStatesofAmerica,2DepartmentofBiochemistryand MolecularBiology,MayoClinicCollegeofMedicine,Rochester,Minnesota,UnitedStatesofAmerica,3DepartmentofObstetricsandGynecology,MayoClinicCollegeof Medicine,Rochester,Minnesota,UnitedStatesofAmerica Abstract Chromosome missegregation in germ cells is an important cause of unexplained infertility, miscarriages, and congenital birth defects in humans. However, the molecular defects that lead to production of aneuploid gametes are largely unknown.Cdc20,theactivatingsubunitoftheanaphase-promotingcomplex/cyclosome(APC/C),initiatessister-chromatid separation by ordering the destruction of two key anaphase inhibitors, cyclin B1 and securin, at the transition from metaphasetoanaphase.ThephysiologicalsignificanceandfullrepertoireoffunctionsofmammalianCdc20areunclearat present, mainly because of the essential nature of this protein in cell cycle progression. To bypass this problem we generatedhypomorphicmicethatexpresslowamountsofCdc20.Thesemicearehealthyandhaveanormallifespan,but femalesproduceeithernoorveryfewoffspring,despitenormalfolliculogenesisandfertilizationrates.Whenmatedwith wild-typemales,hypomorphicfemalesyieldnearlynormalnumbersoffertilizedeggs,butastheseembryosdevelop,they becomemalformedandrarelyreachtheblastocyststage.Inexploringtheunderlyingmechanism,weuncoverthatthevast majorityoftheseembryoshaveabnormalchromosomenumbers,primarilyduetochromosomelaggingandchromosome misalignment during meiosis I in the oocyte. Furthermore, cyclin B1, cyclin A2, and securin are inefficiently degraded in metaphase I; and anaphase I onset is markedly delayed. These results demonstrate that the physiologically effective thresholdlevelofCdc20ishighforfemalemeiosisIandidentifyCdc20hypomo