Document Detail


Cdc20 is critical for meiosis I and fertility of female mice.
MedLine Citation:
PMID:  20941357     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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, the activating subunit of the anaphase-promoting complex/cyclosome (APC/C), initiates sister-chromatid separation by ordering the destruction of two key anaphase inhibitors, cyclin B1 and securin, at the transition from metaphase to anaphase. The physiological significance and full repertoire of functions of mammalian Cdc20 are unclear at present, mainly because of the essential nature of this protein in cell cycle progression. To bypass this problem we generated hypomorphic mice that express low amounts of Cdc20. These mice are healthy and have a normal lifespan, but females produce either no or very few offspring, despite normal folliculogenesis and fertilization rates. When mated with wild-type males, hypomorphic females yield nearly normal numbers of fertilized eggs, but as these embryos develop, they become malformed and rarely reach the blastocyst stage. In exploring the underlying mechanism, we uncover that the vast majority of these embryos have abnormal chromosome numbers, primarily due to chromosome lagging and chromosome 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 threshold level of Cdc20 is high for female meiosis I and identify Cdc20 hypomorphism as a mechanism for chromosome missegregation and formation of aneuploid gametes.
Authors:
Fang Jin; Masakazu Hamada; Liviu Malureanu; Karthik B Jeganathan; Wei Zhou; Dean E Morbeck; Jan M van Deursen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-09-30
Journal Detail:
Title:  PLoS genetics     Volume:  6     ISSN:  1553-7404     ISO Abbreviation:  PLoS Genet.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-10-13     Completed Date:  2011-01-04     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  101239074     Medline TA:  PLoS Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e1001147     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aneuploidy
Animals
Blastocyst / metabolism,  pathology
Carrier Proteins / metabolism
Cdc20 Proteins
Cell Cycle Proteins / genetics,  metabolism*
Chromosome Segregation
Chromosomes, Mammalian / metabolism
Cyclins / metabolism
Female
Fertility / genetics*
Fertilization
Gene Dosage / genetics
Infertility, Female / genetics
Male
Meiosis*
Metaphase
Mice
Mice, Mutant Strains
Oocytes / metabolism,  pathology
Oogenesis / genetics
Protein Processing, Post-Translational
Securin
Spermatogenesis
Grant Support
ID/Acronym/Agency:
CA96985/CA/NCI NIH HHS; R01 CA096985/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Carrier Proteins; 0/Cdc20 Proteins; 0/Cdc20 protein, mouse; 0/Cell Cycle Proteins; 0/Cyclins; 0/Securin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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