Perez G I, Acton B M, Jurisicova A, Perkins G A, White A, Brown J, Trbovich A M, Kim M-R, Fissore R, Xu J, Ahmady A, D'Estaing S G, Li H, Kagawa W, Kurumizaka H, Yokoyama S, Okada H, Mak T W, Ellisman M H, Casper R F, Tilly J L
Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA.
Cell Death Differ. 2007 Mar;14(3):524-33. doi: 10.1038/sj.cdd.4402050. Epub 2006 Oct 13.
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.
尽管对调控细胞凋亡的特定基因的鉴定一直是深入研究的课题，但对于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影响，至少通过两种不同机制。第一种机制在AKR/J小鼠中表现出来，导致基因组不稳定。这表现为新鲜分离的卵母细胞中大量DNA双链断裂，导致高细胞凋亡易感性以及受精后胚胎发育受损。显微注射Rad51可减少DNA损伤、抑制细胞凋亡并改善胚胎发育。第二种机制在FVB小鼠中表现出来，导致线粒体超微结构出现显著二态性。这与细胞色素c释放和高细胞凋亡易感性相关联，后者可通过丙酮酸处理、Smac/DIABLO缺陷或显微注射“正常”线粒体来抑制。因此，背景遗传变异可通过破坏基因组DNA和线粒体完整性，深刻影响雌性生殖细胞中的细胞凋亡。
