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.
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.
Authors: Malgorzata Klauzinska; Nadia P Castro; Maria Cristina Rangel; Benjamin T Spike; Peter C Gray; Daniel Bertolette; Frank Cuttitta; David Salomon Journal: Semin Cancer Biol Date: 2014-08-19 Impact factor: 15.707
Authors: Andrea Pauli; Megan L Norris; Eivind Valen; Guo-Liang Chew; James A Gagnon; Steven Zimmerman; Andrew Mitchell; Jiao Ma; Julien Dubrulle; Deepak Reyon; Shengdar Q Tsai; J Keith Joung; Alan Saghatelian; Alexander F Schier Journal: Science Date: 2014-01-09 Impact factor: 47.728
Authors: Maxim A Vodyanik; Junying Yu; Xin Zhang; Shulan Tian; Ron Stewart; James A Thomson; Igor I Slukvin Journal: Cell Stem Cell Date: 2010-12-03 Impact factor: 24.633