Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency
Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency
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DOI：
10.1038/5985
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发表时间：
1999-02-01
期刊：
影响因子：
30.8
通讯作者：
Tilly, JL
中科院分区：
文献类型：
--
作者：
Perez, GI;Robles, R;Tilly, JL
雌性哺乳动物在出生时被赋予有限数量的卵母细胞，每个卵母细胞被原始卵泡中的单层体细胞（颗粒细胞）包围（1，2）。大多数卵泡的命运是闭锁变性（1，3），这是一个在女性大约50岁时卵母细胞储备接近耗尽的过程，导致绝经（4，5）。细胞凋亡在卵泡闭锁中具有重要作用（6，7），最近的研究表明，在颗粒细胞（8，9）和卵母细胞（10）中表达的Bax可能是卵巢细胞死亡的中心（6-12）。在这里，我们发现，年轻的成年雌性Bax（-/-）小鼠在其卵巢储备中具有比其野生型姐妹篇多三倍的原始卵泡，并且这种卵泡过多在年龄较大时得以维持，例如20-22个月大的雌性Bax（-/-）小鼠在所有发育阶段都具有数百个卵泡，并表现出卵巢类固醇驱动的子宫肥大。这些观察结果与在老年野生型雌性小鼠中观察到的卵巢和子宫萎缩形成对比。年老的雌性Bax（-/-）小鼠与年轻的成年雄性小鼠一起饲养时不能怀孕;然而，中期II卵母细胞可以从年老的Bax（-/-）雌性小鼠的卵巢中取出，并且黄体形成于外源性促性腺激素超排卵后的卵巢中，并且一些卵母细胞能够进行体外受精和早期胚胎发生。因此，卵巢寿命可以通过选择性地破坏Bax功能来延长，但在年老的Bax（-/-）雌性小鼠中，正常生殖性能的其他方面仍然存在缺陷。
Female mammals are endowed with a finite number of oocytes at birth, each enclosed by a single layer of somatic (granulosa) cells in a primordial follicle(1,2). The fate of most follicles is atretic degeneration(1,3), a process that culminates in near exhaustion of the oocyte reserve at approximately the fifth decade of life in women, leading to menopause(4,5). Apoptosis has a fundamental role in follicular atresia(6,7), and recent studies have shown that Bax, which is expressed in both granulosa cells(8,9) and oocytes(10), may be central to ovarian cell death(6-12). Here we show that young adult female Bax(-/-) mice possess threefold more primordial follicles in their ovarian reserve than their wild-type sisters, and this surfeit of follicles is maintained in advanced chronological age, such that 20-22-month-old female Bax(-/-) mice possess hundreds of follicles at ail developmental stages and exhibit ovarian steroid-driven uterine hypertrophy. These observations contrast with the ovarian and uterine atrophy seen in aged wild-type female mice. Aged female Bax(-/-) mice fail to become pregnant when housed with young adult males; however, metaphase II oocytes can be retrieved from, and corpora lutea form in, ovaries of aged Bax(-/-) females following superovulation with exogenous gonadotropins, and some oocytes are competent for in vitro fertilization and early embryogenesis. Therefore, ovarian lifespan can be extended by selectively disrupting Bax function, but other aspects of normal reproductive performance remain defective in aged Bax(-/-) female mice.