Progesterone and AdipoQ Receptor 11 Links Ras Signaling to Cardiac Development in Zebrafish
Progesterone and AdipoQ Receptor 11 Links Ras Signaling to Cardiac Development in Zebrafish
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黄体酮和 AdipoQ 受体 11 将 Ras 信号转导与斑马鱼心脏发育联系起来
DOI：
10.1161/atvbaha.112.252775
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发表时间：
2012-09-01
影响因子：
8.7
通讯作者：
Chen, Yan
中科院分区：
文献类型：
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作者：
Huang, Heng;Jin, Ting;Chen, Yan
β-Progestrin和adipoQ受体（PAQR）10和PAQR 11是两个高度同源的基因，参与高尔基体中的区室化Ras信号传导。本研究的目的是探讨PAQR 10和PAQR 11的生理功能。方法和结果-我们以斑马鱼为模型系统，分析PAQR 10/PAQR 11的潜在功能。PAQR 10和PAQR 11在斑马鱼胚胎中的表达谱在许多区域是重叠的，但只有PAQR 11在发育中的心脏中表达。在斑马鱼胚胎中，PAQR 11而不是PAQR 10的敲低导致心脏发育缺陷，包括心腔扩张、异常心脏循环、房室垫形成破坏、心脏水肿和血液反流。PAQR 11基因敲低可显著降低心脏发育早期心肌细胞的数量和增殖速率，并改变心肌细胞的形态。由PAQR 11敲低引起的心脏缺陷可以被MEK抑制剂和显性负性Ras表型复制。此外，组成型活性Ras，尤其是位于高尔基体而不是位于质膜的Ras，能够挽救PAQR 11敲低引起的心脏缺陷。结论-这项研究不仅提供了体内证据，证明PAQR 11在心脏形态发生中发挥着关键作用，而且还精确地指出了间隔化Ras信号传导在发育过程中的重要性。（Arterioscler Thromb Vasc Biol.2012; 32：2158-2170.）
Objective-Progesterone and adipoQ receptor (PAQR) 10 and PAQR11 are 2 highly homologous genes involved in compartmentalized Ras signaling in the Golgi apparatus. The aim of this study was to investigate the physiological functions of PAQR10 and PAQR11.Methods and Results-We used zebrafish as a model system to analyze the potential function of PAQR10/PAQR11. The expression profiles of PAQR10 and PAQR11 in zebrafish embryos are overlapping in many areas, but only PAQR11 is expressed in the developing heart. Knockdown of PAQR11 but not PAQR10 in zebrafish embryos causes cardiac developmental defects, including dilation of cardiac chambers, abnormal heart looping, disruption of atrioventricular cushion formation, heart edema, and blood regurgitation. PAQR11 knockdown markedly reduces the number and proliferation rate of cardiomyocytes and alters the morphology of myocardial cells during early heart development. The cardiac defects caused by PAQR11 knockdown can be phenocopied by MEK inhibitors and a dominant negative Ras. Furthermore, constitutively active Ras and especially a Golgi-localized but not a plasma membrane-localized Ras are able to rescue the cardiac defects caused by PAQR11 knockdown.Conclusion-This study not only provides in vivo evidence that PAQR11 plays a critical role in heart morphogenesis but also pinpoints the importance of compartmentalized Ras signaling during development. (Arterioscler Thromb Vasc Biol. 2012; 32:2158-2170.)