Caspase-12 compensates for lack of caspase-2 and caspase-3 in female germ cells
Caspase-12 compensates for lack of caspase-2 and caspase-3 in female germ cells
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DOI：
10.1007/s10495-006-0022-z
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发表时间：
2007-04-01
期刊：
影响因子：
7.2
通讯作者：
Perez, G. I.
中科院分区：
文献类型：
--
作者：
Takai, Y.;Matikainen, T.;Perez, G. I.
此前，我们分析了缺乏 caspase-2 或 caspase-3 的小鼠，并记录了 caspase-2 在发育和化疗诱导的卵母细胞凋亡中的作用。这些数据还揭示了 caspase-3 的可有可无，尽管我们发现这种 caspase 对卵巢颗粒细胞死亡至关重要。由于生殖细胞和颗粒细胞的相互依赖性，本文中我们生成了 caspase-2 和 -3 双突变 (DKO) 小鼠，以评估这两种 caspase 在协调卵母细胞凋亡中如何在功能上相互关联。 DKO 和野生型 (WT) 雌性之间的自发卵母细胞凋亡率没有观察到差异。相反，与 WT 雌性的卵母细胞相比，DKO 雌性的卵母细胞更容易受到 DNA 损伤剂诱导的细胞凋亡的影响。 DKO 卵母细胞对死亡的敏感性增加似乎是对 DNA 损伤的特异性反应，并且与 caspase-12 的代偿性上调相关。有趣的是，DKO 卵母细胞比 WT 卵母细胞对甲氨蝶呤 (MTX) 诱导的细胞凋亡具有更强的抵抗力。这些结果表明，在雌性生殖细胞中，直接干扰其代谢状态的损伤（例如 MTX）需要 caspase-2 和 caspase-3 作为随后的细胞死亡级联的强制刽子手。然而，当涉及 DNA 损伤且缺乏 caspase-2 和 -3 时，caspase-12 就会上调并介导卵母细胞凋亡。
Previously, we analyzed mice lacking either caspase-2 or caspase-3 and documented a role for caspase-2 in developmental and chemotherapy-induced apoptosis of oocytes. Those data also revealed dispensability of caspase-3, although we found this caspase critical for ovarian granulosa cell death. Because of the mutual interdependence of germ cells and granulosa cells, herein we generated caspase-2 and -3 double-mutant (DKO) mice to evaluate how these two caspases functionally relate to each other in orchestrating oocyte apoptosis. No difference was observed in the rate of spontaneous oocyte apoptosis between DKO and wildtype (WT) females. In contrast, the oocytes from DKO females were more susceptible to apoptosis induced by DNA damaging agents, compared with oocytes from WT females. This increased sensitivity to death of DKO oocytes appears to be a specific response to DNA damage, and it was associated with a compensatory upregulation of caspase-12. Interestingly, DKO oocytes were more resistant to apoptosis induced by methotrexate (MTX) than WT oocytes. These results revealed that in female germ cells, insults that directly interfere with their metabolic status (e.g. MTX) require caspase-2 and caspase-3 as obligatory executioners of the ensuing cell death cascade. However, when DNA damage is involved, and in the absence of caspase-2 and -3, caspase-12 becomes upregulated and mediates apoptosis in oocytes.