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.

نویسندگان

  • Cristina D'Aniello
  • Enza Lonardo
  • Salvatore Iaconis
  • Ombretta Guardiola
  • Anna Maria Liguoro
  • Giovanna L Liguori
  • Monica Autiero
  • Peter Carmeliet
  • Gabriella Minchiotti
چکیده

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.

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عنوان ژورنال:
  • Circulation research

دوره 105 3  شماره 

صفحات  -

تاریخ انتشار 2009