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, 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.
Highlights
Mitotic checkpoint genes are believed to be prime targets for deregulation in human infertility [1]
We identify Cdc20, a critical activator of the anaphase-promoting complex or cyclosome (APC/C) E3 ubiquitin ligase that initiates sister chromosome separation by ordering the destruction of cyclin B1 and securin, as a female infertility gene
We found that the time from germinal vesicle breakdown (GVBD) to metaphase was similar in Cdc20+/+ and Cdc202/H oocytes (Figure 6A and 6B), which is consistent with the notion that Cdh1 functions as the primary ACP/C activator during the early stages of meiosis I [12]
Summary
Mitotic checkpoint genes are believed to be prime targets for deregulation in human infertility [1]. At early stages of mitosis, various mitotic checkpoint proteins, including members of the Bub and Mad protein families, concentrate at unattached kinetochores to generate a diffusible signal that inhibits the anaphase-promoting complex or cyclosome (APC/C), a large E3 ubiquitin ligase that drives metaphase-toanaphase transition by catalyzing the ubiquitination and degradation of cyclin B1 and securin [3]. The exact composition of the inhibitory signal remains a major subject of investigation, it is believed to contain Bub3-bound BubR1 and Mad that has been primed by kinetochore-associated Mad1Mad to stably interact with the APC/C activating subunit Cdc20 [4,5,6]. Upon attachment and alignment of the last chromosome pair, the inhibitory signal is quenched and APC/C activated through release of Cdc inhibition, triggering the ubiquitination and destruction of cyclin B1 and securin. A protease that is held in an inactive state by securin and cyclin B1/Cdk, is allowed to cleave the Scc subunit of the cohesin complex that holds sister chomatids together, inducing the physical separation of sister chromatids by spindle forces [7,8]
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