Mahtab Edris A F, Wijffels Maurits C E F, Van Den Akker Nynke M S, Hahurij Nathan D, Lie-Venema Heleen, Wisse Lambertus J, Deruiter Marco C, Uhrin Pavel, Zaujec Jan, Binder Bernd R, Schalij Martin J, Poelmann Robert E, Gittenberger-De Groot Adriana C
Department of Anatomy and Embryology, Leiden University Medical Center, The Netherlands.
Dev Dyn. 2008 Mar;237(3):847-57. doi: 10.1002/dvdy.21463.
Epicardium and epicardium-derived cells have been shown to be necessary for myocardial differentiation. To elucidate the function of podoplanin in epicardial development and myocardial differentiation, we analyzed podoplanin knockout mouse embryos between embryonic day (E) 9.5 and E15.5 using immunohistochemical differentiation markers, morphometry, and three-dimensional reconstructions. Podoplanin null mice have an increased embryonic lethality, possibly of cardiac origin. Our study reveals impairment in the development of the proepicardial organ, epicardial adhesion, and spreading and migration of the epicardium-derived cells. Mutant embryos show a hypoplastic and perforated compact and septal myocardium, hypoplastic atrioventricular cushions resulting in atrioventricular valve abnormalities, as well as coronary artery abnormalities. The epicardial pathology is correlated with reduced epithelial-mesenchymal transformation caused by up-regulation of E-cadherin, normally down-regulated by podoplanin. Our results demonstrate a role for podoplanin in normal cardiac development based on epicardial-myocardial interaction. Abnormal epicardial differentiation and reduced epithelial-mesenchymal transformation result in deficient epicardium-derived cells leading to myocardial pathology and cardiac anomalies.
心外膜和源自心外膜的细胞已被证明是心肌分化所必需的。为了阐明血小板反应蛋白在心脏外膜发育和心肌分化中的功能，我们使用免疫组织化学分化标记、形态测量学和三维重建技术，分析了胚胎第（E）9.5天至E15.5天之间的血小板反应蛋白基因敲除小鼠胚胎。血小板反应蛋白基因敲除小鼠的胚胎致死率增加，可能源于心脏。我们的研究揭示了心外膜器官发育、心外膜黏附以及源自心外膜的细胞的扩散和迁移存在缺陷。突变胚胎显示致密和间隔心肌发育不全且有穿孔，房室垫发育不全导致房室瓣异常，以及冠状动脉异常。心外膜病理与E-钙黏蛋白上调导致的上皮-间质转化减少相关，而E-钙黏蛋白通常由血小板反应蛋白下调。我们的结果表明，基于心外膜-心肌相互作用，血小板反应蛋白在正常心脏发育中发挥作用。心外膜分化异常和上皮-间质转化减少导致源自心外膜的细胞不足，进而导致心肌病理和心脏异常。
