Cdc20 is critical for meiosis I and fertility of female mice.
Cdc20 is critical for meiosis I and fertility of female mice.
复制标题
DOI：
10.1371/journal.pgen.1001147
复制
发表时间：
2010-09-30
期刊：
影响因子：
4.5
通讯作者：
van Deursen JM
中科院分区：
文献类型：
--
作者：
Jin F;Hamada M;Malureanu L;Jeganathan KB;Zhou W;Morbeck DE;van Deursen JM
生殖细胞中的染色体错误分离是人类不明原因不孕、流产和先天性出生缺陷的重要原因。然而，导致非整倍体配子产生的分子缺陷在很大程度上是未知的。Cdc 20是后期促进复合物/细胞周期体（APC/C）的激活亚基，通过在中期到后期的过渡期破坏两种关键的后期抑制剂细胞周期蛋白B1和securin来启动姐妹染色单体分离。哺乳动物Cdc 20的生理意义和全部功能目前尚不清楚，主要是因为这种蛋白质在细胞周期进程中的基本性质。为了绕过这个问题，我们产生了表达少量Cdc 20的亚型小鼠。这些小鼠是健康的，有正常的寿命，但女性产生要么没有或很少的后代，尽管正常的卵泡发育和受精率。当与野生型雄性交配时，亚纯型雌性产生接近正常数量的受精卵，但随着这些胚胎的发育，它们变得畸形，很少达到囊胚阶段。在探索潜在的机制，我们发现，这些胚胎中的绝大多数有异常的染色体数目，主要是由于染色体落后和染色体错位在减数分裂I的卵母细胞。此外，细胞周期蛋白B1，细胞周期蛋白A2，和securin是无效的中期I降解，后期I发作显着延迟。这些结果表明，生理上有效的阈值水平的Cdc 20是高的女性减数分裂I和确定Cdc 20亚型染色体误分离和形成非整倍体配子的机制。非整倍体，染色体数目异常，是精子和卵细胞中常见的缺陷，导致人类不育、流产和先天性出生缺陷。虽然这些发育结果在人类生殖中很普遍，但对可能导致生殖细胞非整倍体的分子缺陷知之甚少。在这项研究中，我们确定Cdc 20，APC/C E3泛素连接酶的关键激活剂，启动姐妹染色体分离，通过订购破坏细胞周期蛋白B1和securin，作为女性不育基因。我们发现，Cdc 20含量低的雌性小鼠具有正常的适应性，但几乎只产生非整倍体胚胎，这些胚胎无法茁壮成长并在发育早期死亡。非整倍体主要是由于原代卵母细胞中的染色体分离错误，这可能是由中期I期间APC/C介导的有丝分裂周期蛋白和securin的无效破坏引起的。因此，我们的研究表明，初级卵母细胞高度依赖于Cdc 20的准确染色体分离，并提高了Cdc 20不足可能是其他健康女性不孕症的原因的可能性。
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. Aneuploidy, an abnormal number of chromosomes, is a common defect in sperm and egg cells that is responsible for human infertility, miscarriage, and congenital birth defects. Although these developmental outcomes are prevalent in human reproduction, little is known about the molecular defects that may cause aneuploidy in germ cells. In this study, we identify Cdc20, a critical activator of the 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 show that female mice with low amounts of Cdc20 have normal fitness but almost exclusively produce aneuploid embryos that fail to thrive and die early in development. The aneuploidy primarily results from chromosome segregation errors in primary oocytes that may be caused by inefficient APC/C-mediated destruction of mitotic cyclins and securin during metaphase I. Thus, our studies reveal that primary oocytes are highly dependent on Cdc20 for accurate chromosome segregation and raise the possibility that Cdc20 insufficiency may be a cause of infertility in otherwise healthy women.
登录
查看更多内容
影响因子：
11.8
作者：
Malureanu, Liviu A.;Jeganathan, Karthik B.;Hamada, Masakazu;Wasilewski, Lisa;Davenport, James;van Deursen, Jan M.
通讯作者：
van Deursen, Jan M.
DOI：
10.1038/nrm2718
发表时间：
2009-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1083/jcb.200706015
发表时间：
2007-10-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jeganathan K;Malureanu L;Baker DJ;Abraham SC;van Deursen JM
通讯作者：
van Deursen JM
Cdc20在哺乳动物细胞中的动力学和中心体的CDC20的快速微管动力学。
影响因子：
7.8
作者：
Kallio, Marko J;Beardmore, Victoria A;Weinstein, Jasminder;Gorbsky, Gary J
通讯作者：
Gorbsky, Gary J
影响因子：
3.8
作者：
Homer, HA;McDougall, A;Herbert, M
通讯作者：
Herbert, M