Loss of Aif function causes cell death in the mouse embryo, but the temporal progression of patterning is normal
Loss of Aif function causes cell death in the mouse embryo, but the temporal progression of patterning is normal
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DOI：
10.1073/pnas.0603950103
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发表时间：
2006-06-27
影响因子：
11.1
通讯作者：
Martin, Gail R.
中科院分区：
文献类型：
--
作者：
Brown, Doris;Yu, Benjamin D.;Martin, Gail R.
凋亡诱导因子（Apoptosis-inducing factor，AIF）是一种进化上保守的、广泛表达的黄素蛋白，具有NADH氧化酶活性，通常局限于线粒体。在哺乳动物细胞中，AIF响应于细胞凋亡刺激而从线粒体释放，并易位到细胞核，在那里它被认为结合DNA并以不依赖半胱天冬酶的方式促进染色质溶解和细胞死亡。在这里，我们描述了在早期小鼠胚胎中灭活AIF的后果。出乎意料的是，我们发现，无论是在拟胚体和细胞凋亡相关的胚胎神经管关闭的空泡化依赖过程中发生的AIF的情况下，表明AIF功能是不需要在早期小鼠胚胎的凋亡细胞死亡。到胚胎第9天（E9），Aif功能的丧失导致细胞异常死亡，可能是因为线粒体呼吸链复合物I活性降低。由于这种细胞死亡，Aif无效胚胎在E9后不能显著增加大小。值得注意的是，图案化过程基本上以正常的时间表继续进行，使得仅具有约1/10正常细胞数的E10 Aif无效胚胎具有与其野生型同窝仔相同的体节数。这些观察结果表明，小鼠的模式形成可以独立于胚胎大小和细胞数量而发生。
Apoptosis-inducing factor (AIF) is an evolutionarily conserved, ubiquitously expressed flavoprotein with NADH oxidase activity that is normally confined to mitochondria. In mammalian cells, AIF is released from mitochondria in response to apoptotic stimuli and translocates to the nucleus where it is thought to bind DNA and contribute to chromatinolysis and cell death in a caspase-independent manner. Here we describe the consequences of inactivating Aif in the early mouse embryo. Unexpectedly, we found that both the apoptosis-dependent process of cavitation in embryoid bodies and apoptosis associated with embryonic neural tube closure occur in the absence of AIF, indicating that Aif function is not required for apoptotic cell death in early mouse embryos. By embryonic day 9 (E9), loss of Aif function causes abnormal cell death, presumably because of reduced mitochondrial respiratory chain complex I activity. Because of this cell death, Aif null embryos fail to increase significantly in size after E9. Remarkably, patterning processes continue on an essentially normal schedule, such that E10 Aif null embryos with only approximate to 1/10 the normal number of cells have the same somite number as their wild-type littermates. These observations show that pattern formation in the mouse can occur independent of embryo size and cell number.