Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure
Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure
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DOI：
10.1038/sj.cdd.4402050
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发表时间：
2007-03-01
影响因子：
12.4
通讯作者：
Tilly, J. L.
中科院分区：
文献类型：
--
作者：
Perez, G. I.;Acton, B. M.;Tilly, J. L.
虽然鉴定调控细胞凋亡的特定基因一直是一个热门的研究课题，但背景遗传变异在调节细胞死亡中所起的作用却知之甚少。利用来自近交系小鼠品系的生殖细胞，我们发现成熟（中期II）卵母细胞中的细胞凋亡受遗传背景的影响，通过至少两种不同的机制。第一个，表现在AKR/J小鼠中，导致基因组不稳定性。这反映在新鲜分离的卵母细胞中的大量DNA双链断裂，导致受精后的高凋亡易感性和受损的胚胎发育。显微注射Rad 51可减少DNA损伤，抑制细胞凋亡，改善胚胎发育。第二，表现在FVB小鼠，结果在线粒体超微结构的显着二型。这与细胞色素c释放和高凋亡敏感性相关，后者被丙酮酸处理、Smac/DIABLO缺陷或“正常”线粒体的显微注射抑制。因此，背景遗传变异可以通过破坏基因组DNA和线粒体完整性来深刻影响雌性生殖细胞的凋亡。
Although the identification of specific genes that regulate apoptosis has been a topic of intense study, little is known of the role that background genetic variance plays in modulating cell death. Using germ cells from inbred mouse strains, we found that apoptosis in mature (metaphase II) oocytes is affected by genetic background through at least two different mechanisms. The first, manifested in AKR/J mice, results in genomic instability. This is reflected by numerous DNA double- strand breaks in freshly isolated oocytes, causing a high apoptosis susceptibility and impaired embryonic development following fertilization. Microinjection of Rad51 reduces DNA damage, suppresses apoptosis and improves embryonic development. The second, manifested in FVB mice, results in dramatic dimorphisms in mitochondrial ultrastructure. This is correlated with cytochrome c release and a high apoptosis susceptibility, the latter of which is suppressed by pyruvate treatment, Smac/DIABLO deficiency, or microinjection of 'normal' mitochondria. Therefore, background genetic variance can profoundly affect apoptosis in female germ cells by disrupting both genomic DNA and mitochondrial integrity.