Geminin is essential for the development of preimplantation mouse embryos
Geminin is essential for the development of preimplantation mouse embryos
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DOI：
10.1111/j.1365-2443.2006.01019.x
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发表时间：
2006-11-01
期刊：
影响因子：
2.1
通讯作者：
Nakayama, Keiko
中科院分区：
文献类型：
--
作者：
Hara, Kentaro;Nakayama, Keiichi I.;Nakayama, Keiko
DNA的复制受到严格控制，以确保每个细胞周期只发生一次。双黄素被认为是这一许可机制的核心调节因子，通过结合和拮抗CDT1的功能，从而防止在S和G(2)期的重复复制。我们现在已经产生了缺乏双黄素的小鼠，以阐明这种蛋白质在发育过程中的生理作用。缺乏双黄素被证明会导致植入前死亡。纯合子突变胚胎的发育延迟首先出现在从4-细胞期到8-细胞期的过渡阶段，伴随着母体双生蛋白的消失，发育在8-细胞期停止。突变的胚胎表现出形态异常，如分散的卵裂球，核的大小和形状都不规则，以及细胞与细胞的粘附力受损。突变的胚胎发生了DNA复制，但没有检测到有丝分裂。异常的卵裂球含有受损的DNA，并经历细胞凋亡，这可能是DNA复制放松调控的结果。我们的结果表明，在小鼠发育的植入前阶段，双黄素对于细胞周期从S期到M期的协同发展是必不可少的。
Replication of DNA is strictly controlled to ensure that it occurs only once per cell cycle. Geminin has been thought to serve as a central mediator of this licensing mechanism by binding to and antagonizing the function of Cdt1 and thereby preventing re-replication during S and G(2) phases. We have now generated mice deficient in geminin to elucidate the physiologic role of this protein during development. Lack of geminin was shown to result in preimplantation mortality. A delay in the development of homozygous mutant embryos was first apparent at the transition from the four- to eight-cell stages, concomitant with the disappearance of maternal geminin protein, and development was arrested at the eight-cell stage. The mutant embryos manifest morphological abnormalities such as dispersed blastomeres with nuclei that are irregular both in size and shape as well as impaired cell-cell adhesion. DNA replication occurs but mitosis was not detected in the mutant embryos. The abnormal blastomeres contain damaged DNA and undergo apoptosis, likely as a consequence of the deregulation of DNA replication. Our results suggest that geminin is essential for cooperative progression of the cell cycle through S phase to M phase during the preimplantation stage of mouse development.