Small heat shock proteins Hspb7 and Hspb12 regulate early steps of cardiac morphogenesis.
Small heat shock proteins Hspb7 and Hspb12 regulate early steps of cardiac morphogenesis.
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DOI：
10.1016/j.ydbio.2013.06.025
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发表时间：
2013-09-15
影响因子：
2.7
通讯作者：
Evans, Todd
中科院分区：
文献类型：
--
作者：
Rosenfeld, Gabriel E.;Mercer, Emily J.;Mason, Christopher E.;Evans, Todd
心脏形态发生是一个复杂的多阶段过程，控制不同步骤的分子基础仍然知之甚少。由于gata 4编码形态发生的关键转录调节因子，我们分析了当Gata 4蛋白从发育中的斑马鱼胚胎中耗尽时心肌细胞中的转录变化。我们发现gata 4调节两个小的热休克基因hspb 7和hspb 12的表达，这两个基因都在胚胎心脏中表达。我们发现，热休克蛋白B7或热休克蛋白B12的耗竭破坏了正常的心脏形态发生，至少部分是由于心室大小和形状的缺陷。我们证实了gata 4在遗传上与hspb 7/12通路相互作用，但令人惊讶的是，我们发现hspb 7也有一个更早的，不依赖gata 4的功能。耗尽扰乱枯否氏囊泡（KV）形态，导致建立左右轴不对称失败。卵黄合胞体层中Hspb 7的靶向消耗足以破坏KV形态，并且还导致甚至更早的心管形成阻断和双稳态表型。近年来，多项全基因组关联研究发现，HSPB 7单核苷酸多态性与特发性心肌病和心力衰竭高度相关。因此，GATA 4和HSPB 7可能单独或共同调节与先天性和获得性人类心脏病相关的形态发生。
Cardiac morphogenesis is a complex multi-stage process, and the molecular basis for controlling distinct steps remains poorly understood. Because gata4 encodes a key transcriptional regulator of morphogenesis, we profiled transcript changes in cardiomyocytes when Gata4 protein is depleted from developing zebrafish embryos. We discovered that gata4 regulates expression of two small heat shock genes, hspb7 and hspb12, both of which are expressed in the embryonic heart. We show that depletion of Hspb7 or Hspb12 disrupts normal cardiac morphogenesis, at least in part due to defects in ventricular size and shape. We confirmed that gata4 interacts genetically with the hspb7/12 pathway, but surprisingly, we found that hspb7 also has an earlier, gata4-independent function. Depletion perturbs Kupffer’s vesicle (KV) morphology leading to a failure in establishing the left-right axis of asymmetry. Targeted depletion of Hspb7 in the yolk syncytial layer is sufficient to disrupt KV morphology and also causes an even earlier block to heart tube formation and a bifid phenotype. Recently, several genome-wide association studies found that HSPB7 SNPs are highly associated with idiopathic cardiomyopathies and heart failure. Therefore, GATA4 and HSPB7 may act alone or together to regulate morphogenesis with relevance to congenital and acquired human heart disease.
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DOI：
10.1073/pnas.1016959108
发表时间：
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影响因子：
11.1
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