Non-muscle myosin IIB (Myh10) is required for epicardial function and coronary vessel formation during mammalian development.
Non-muscle myosin IIB (Myh10) is required for epicardial function and coronary vessel formation during mammalian development.
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DOI：
10.1371/journal.pgen.1007068
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发表时间：
2017-10
期刊：
影响因子：
4.5
通讯作者：
Hentges KE
中科院分区：
文献类型：
--
作者：
Ridge LA;Mitchell K;Al-Anbaki A;Shaikh Qureshi WM;Stephen LA;Tenin G;Lu Y;Lupu IE;Clowes C;Robertson A;Barnes E;Wright JA;Keavney B;Ehler E;Lovell SC;Kadler KE;Hentges KE
冠状动脉血管系统是向心脏提供血液供应的基本血管网络。冠状动脉血流的中断会导致心脏病，这是全球过早死亡的主要原因。心血管疾病的治疗方法的产生将有助于更深入地了解支持冠状动脉血管形成的发育过程。从ENU诱变筛选，我们已经分离出一个小鼠突变显示胚胎脑积水和心脏缺陷（EHC）。定位克隆和候选基因分析表明，EHC表型的结果从一个点突变的Myh 10基因，编码NMHC IIB的剪接供体位点。互补检测证实Myh 10突变导致EHC表型。EHC心脏缺陷的表征显示心肌发育异常，与先前生成的NMHC IIB无效小鼠系的观察结果一致。对EHC突变心脏的分析也发现了冠状动脉血管形成的缺陷。我们将冠状动脉血管异常归因于心外膜细胞功能缺陷，因为EHC心外膜显示出异常的细胞形态，经历上皮-间质转化（EMT）的能力降低，以及心外膜衍生细胞（EPDC）迁移到心肌中受损。我们对EHC突变体的研究表明，NMHC IIB在心外膜功能和冠状动脉血管形成中的需求，突出了这种蛋白质在心脏发育和最终胚胎存活中的重要性。为了使心脏正常工作，它必须有自己的血液供应。血液通过称为冠状血管系统的血管系统输送到心脏。在发育过程中，一些形成冠状血管的细胞起源于心外膜，即心脏的外层。这些心外膜来源的细胞迁移到心脏组织中，在那里它们有助于冠状血管网络的形成。我们已经发现，一个小鼠突变基因Myh 10，编码的细胞骨架蛋白非肌肉肌球蛋白IIB，未能形成冠状动脉血管。我们的工作揭示了心外膜的缺陷，这导致了这种突变体冠状动脉血管发育的缺乏。令人惊讶的是，我们发现，虽然突变的心外膜细胞在从胚胎中提取时能够运动，但这些细胞在胚胎心脏发育的背景下无法动员成血管网络。我们认为，这种迁移失败是由于异常的细胞外环境中的突变心脏。这项工作突出了Myh 10基因在冠状动脉血管形成的关键发育过程中的重要性。
The coronary vasculature is an essential vessel network providing the blood supply to the heart. Disruptions in coronary blood flow contribute to cardiac disease, a major cause of premature death worldwide. The generation of treatments for cardiovascular disease will be aided by a deeper understanding of the developmental processes that underpin coronary vessel formation. From an ENU mutagenesis screen, we have isolated a mouse mutant displaying embryonic hydrocephalus and cardiac defects (EHC). Positional cloning and candidate gene analysis revealed that the EHC phenotype results from a point mutation in a splice donor site of the Myh10 gene, which encodes NMHC IIB. Complementation testing confirmed that the Myh10 mutation causes the EHC phenotype. Characterisation of the EHC cardiac defects revealed abnormalities in myocardial development, consistent with observations from previously generated NMHC IIB null mouse lines. Analysis of the EHC mutant hearts also identified defects in the formation of the coronary vasculature. We attribute the coronary vessel abnormalities to defective epicardial cell function, as the EHC epicardium displays an abnormal cell morphology, reduced capacity to undergo epithelial-mesenchymal transition (EMT), and impaired migration of epicardial-derived cells (EPDCs) into the myocardium. Our studies on the EHC mutant demonstrate a requirement for NMHC IIB in epicardial function and coronary vessel formation, highlighting the importance of this protein in cardiac development and ultimately, embryonic survival. In order for the heart to function properly it must have its own blood supply. Blood is delivered to the heart through a system of vessels called the coronary vasculature. During development, some of the cells that form the coronary vessels originate from the epicardium, the outer layer of the heart. These epicardial-derived cells migrate into the cardiac tissue where they contribute to the formation of the coronary vascular network. We have found that a mouse mutant containing a mutation in the gene Myh10, which encodes the cytoskeletal protein non-muscle myosin IIB, fails to form the coronary vasculature. Our work reveals defects in the epicardium, which contribute to the lack of coronary vessel development in this mutant. Surprisingly, we discovered that whilst the mutant epicardial cells are capable of movement when extracted from the embryo, these cells fail to mobilise into a vascular network in the context of the developing embryonic heart. We propose that this migration failure is due to abnormalities in the extracellular environment in the mutant heart. This work highlights the importance of the Myh10 gene in the critical developmental process of coronary vessel formation.
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