Loss of Apaf-1 leads to partial rescue of the HAND2-null phenotype
Loss of Apaf-1 leads to partial rescue of the HAND2-null phenotype
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DOI：
10.1016/j.ydbio.2004.11.001
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发表时间：
2005-02-01
影响因子：
2.7
通讯作者：
Srivastava, D
中科院分区：
文献类型：
--
作者：
Aiyer, AR;Honarpour, N;Srivastava, D
HAND 2是心脏、咽弓和肢体发育所必需的转录因子。HAND 2缺失胚胎中的细胞凋亡导致右心室和咽弓发育不全，导致胚胎第10.0天（E）因心力衰竭致死。为了研究细胞凋亡在诱导HAND 2无效表型中的作用，我们产生了缺乏HAND 2和Apaf-1的小鼠胚胎，Apaf-1是线粒体损伤诱导细胞凋亡的中心下游介质。与HAND 2（-/-）胚胎相反，E10.5-11.0的HAND 2（-/-）Apaf-1（-/-）胚胎具有发育良好的咽弓、主动脉弓动脉，并且没有心力衰竭的迹象。通过HAND 2（-/-）Apaf-1（-/-）胚胎咽弓的TUNEL分析显示细胞凋亡减少，胚胎有明显开放的主动脉弓动脉。然而，与HAND 2（-/-）胚胎相比，这些动物的心室发育不全和细胞死亡没有变化，导致E11.0时生长停滞。我们的研究表明，咽弓间充质中HAND 2的缺失以Apaf-1依赖的方式导致细胞凋亡，而主动脉弓完整性的缺失导致早期死亡，心室缺陷与主动脉弓的发育无关。(C)2004年爱思唯尔公司All rights reserved.
HAND2 is an essential transcription factor for cardiac, pharyngeal arch, and limb development. Apoptosis in the HAND2-null embryo causes hypoplasia of the right ventricle and pharyngeal arches leading to lethality by embryonic day (E) 10.0 from heart failure. In order to investigate the role of apoptosis in inducing the HAND2-null phenotype, we generated mouse embryos lacking both HAND2 and Apaf-1, a central downstream mediator of mitochondrial damage-induced apoptosis. In contrast to HAND2(-/-) embryos, HAND2(-/-) Apaf-1(-/-) embryos at E10.5-11.0 had well-developed pharyngeal arches, aortic arch arteries, and no signs of cardiac failure. TUNEL analysis through pharyngeal arches of HAND2(-/-) Apaf-1(-/-) embryos revealed decreased apoptosis and the embryos had clearly patent aortic arch arteries. However, ventricular hypoplasia and cell death were unchanged in these animals compared to HAND2(-/-) embryos, resulting, in growth arrest at E11.0. Our study suggests that loss of HAND2 in the pharyngeal arch mesenchyme leads to apoptosis in an Apaf-1-dependent fashion and that, while loss of aortic arch integrity contributes to the early lethality, the ventricular defects are independent of arch development. (C) 2004 Elsevier Inc. All rights reserved.