D'Aniello Cristina, Lonardo Enza, Iaconis Salvatore, Guardiola Ombretta, Liguoro Anna Maria, Liguori Giovanna L, Autiero Monica, Carmeliet Peter, Minchiotti Gabriella
Institute of Genetics and Biophysics "A. Buzzati-Traverso," CNR, Via Pietro Castellino 111, 80131 Naples, Italy.
Circ Res. 2009 Jul 31;105(3):231-8. doi: 10.1161/CIRCRESAHA.109.201186. Epub 2009 Jul 2.
Pluripotent stem cells represent a powerful model system to study the early steps of cardiac specification for which the molecular control is largely unknown. The EGF-CFC (epidermal growth factor-Cripto/FRL-1/Cryptic) Cripto protein is essential for cardiac myogenesis in embryonic stem cells (ESCs).
Here, we study the role of apelin and its G protein-coupled receptor, APJ, as downstream targets of Cripto both in vivo and in ESC differentiation.
Gain-of-function experiments show that APJ suppresses neuronal differentiation and restores the cardiac program in Cripto(-/-) ESCs. Loss-of-function experiments point for a central role for APJ/apelin in the gene regulatory cascade promoting cardiac specification and differentiation in ESCs. Remarkably, we show for the first time that apelin promotes mammalian cardiomyogenesis via activation of mitogen-activated protein kinase/p70S6 through coupling to a Go/Gi protein.
Together our data provide evidence for a previously unrecognized function of APJ/apelin in the Cripto signaling pathway governing mesoderm patterning and cardiac specification in mammals.
多能干细胞是研究心脏特化早期步骤的强大模型系统，而其分子调控在很大程度上尚不清楚。表皮生长因子-Cripto/FRL-1/隐窝蛋白（EGF-CFC）家族的Cripto蛋白对于胚胎干细胞（ESC）中的心肌生成至关重要。
在此，我们研究apelin及其G蛋白偶联受体APJ作为Cripto在体内和ESC分化中的下游靶点的作用。
功能获得实验表明，APJ抑制神经元分化并恢复Cripto基因敲除（-/-）ESC中的心脏程序。功能丧失实验表明，APJ/apelin在促进ESC心脏特化和分化的基因调控级联中起核心作用。值得注意的是，我们首次表明，apelin通过与Go/Gi蛋白偶联激活丝裂原活化蛋白激酶/p70S6来促进哺乳动物心肌生成。
我们的数据共同为APJ/apelin在哺乳动物中控制中胚层模式和心脏特化的Cripto信号通路中以前未被认识的功能提供了证据。
