Published online before print July 2, 2009, doi: 10.1161/CIRCRESAHA.109.201186
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Submitted on September 16, 2008
Revised on June 22, 2009
Accepted on June 23, 2009
G Protein–Coupled Receptor APJ and Its Ligand Apelin Act Downstream of Cripto to Specify Embryonic Stem Cells Toward the Cardiac Lineage Through Extracellular Signal-Regulated Kinase/p70S6 Kinase Signaling Pathway
Cristina D'Aniello ;
From the Stem Cell Fate Laboratory (C.D., E.L., S.I., O.G., G.M.), Institute of Genetics and Biophysics "A. Buzzati-Traverso," Consiglio Nazionale delle Ricerche, Naples, Italy; Institute of Genetics and Biophysics "A. Buzzati-Traverso" (C.D., E.L., S.I., O.G., A.M.L., G.L.L., G.M.), Consiglio Nazionale delle Ricerche, Naples, Italy; Vesalius Research Center (M.A., P.C.), VIB, Leuven, Belgium; and Vesalius Research Center (P.C.), Katholieke Universiteit Leuven, Belgium.
* To whom correspondence should be addressed. E-mail: minchiot{at}igb.cnr.it.
Rationale: 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).
Objective: Here, we identify apelin and its G protein–coupled receptor, APJ, as downstream targets of Cripto both in vivo and in ESC differentiation.
Methods and Results: 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.
Conclusions: 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.
Key words: embryonic stem cells • cardiomyogenesis • cripto • apelini • APJ/msr1
Related Article:
- Why Don't They Beat?: Cripto, Apelin/APJ, and Myocardial Differentiation
- Margaret L. Kirby
Circ. Res. 2009 105: 211-213.[Extract] [Full Text] [PDF]
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  M. L. Kirby Why Don't They Beat?: Cripto, Apelin/APJ, and Myocardial Differentiation Circ. Res., July 31, 2009; 105(3): 211 - 213. [Full Text] [PDF]
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