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(Circulation Research. 2009;105:231.)
© 2009 American Heart Association, Inc.

Molecular Medicine

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, Enza Lonardo, Salvatore Iaconis, Ombretta Guardiola, Anna Maria Liguoro, Giovanna L. Liguori, Monica Autiero, Peter Carmeliet, Gabriella Minchiotti

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.

Correspondence to Gabriella Minchiotti, Institute of Genetics and Biophysics "A. Buzzati-Traverso," CNR, Via Pietro Castellino 111, 80131 Naples, Italy. 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 study the role of 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 • apelin • APJ/msr1

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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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