Autophagy is essential for cardiac morphogenesis during vertebrate development
Autophagy is essential for cardiac morphogenesis during vertebrate development
复制标题
DOI：
10.4161/auto.27649
复制
发表时间：
2014-04-01
期刊：
影响因子：
13.3
通讯作者：
Amatruda, James F.
中科院分区：
文献类型：
--
作者：
Lee, Eunmyong;Koo, Yeon;Amatruda, James F.
遗传分析表明，自噬是一种进化上保守的溶酶体降解途径，对真核细胞的分化和发育至关重要。然而，很少有人知道自噬是否有助于胚胎发生过程中的形态发生。为了解决这个问题，我们研究了自噬在斑马鱼早期发育中的作用，斑马鱼是研究脊椎动物组织和器官形态发生的模式生物。使用转基因表达荧光自噬报告蛋白GFP-LC 3的斑马鱼，我们发现自噬在胚胎期的多个组织中是活跃的，包括心脏。通过morpholino敲低必需的自噬基因（包括atg 5，atg 7和becn 1）来抑制自噬，导致形态发生缺陷，死亡细胞数量增加，心脏结构异常，生物体存活率降低。对自噬缺陷斑马鱼心脏发育的进一步分析揭示了心脏成环缺陷、异常腔室形态、异常瓣膜发育和关键转录因子（包括foxn 4、tbx 5和tbx 2）的异位表达。与这些结果相一致，Atg 5缺陷小鼠显示Tbx 2表达异常，瓣膜发育和室分隔缺陷。因此，自噬在脊椎动物发育过程中的心脏形态发生中起着重要的、保守的作用。
Genetic analyses indicate that autophagy, an evolutionarily conserved lysosomal degradation pathway, is essential for eukaryotic differentiation and development. However, little is known about whether autophagy contributes to morphogenesis during embryogenesis. To address this question, we examined the role of autophagy in the early development of zebrafish, a model organism for studying vertebrate tissue and organ morphogenesis. Using zebrafish that transgenically express the fluorescent autophagy reporter protein, GFP-LC3, we found that autophagy is active in multiple tissues, including the heart, during the embryonic period. Inhibition of autophagy by morpholino knockdown of essential autophagy genes (including atg5, atg7, and becn1) resulted in defects in morphogenesis, increased numbers of dead cells, abnormal heart structure, and reduced organismal survival. Further analyses of cardiac development in autophagy-deficient zebrafish revealed defects in cardiac looping, abnormal chamber morphology, aberrant valve development, and ectopic expression of critical transcription factors including foxn4, tbx5, and tbx2. Consistent with these results, Atg5-deficient mice displayed abnormal Tbx2 expression and defects in valve development and chamber septation. Thus, autophagy plays an essential, conserved role in cardiac morphogenesis during vertebrate development.