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

Circ Res. 2009 Jul 31;105(3):231-8. doi: 10.1161/CIRCRESAHA.109.201186. Epub 2009 Jul 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines
  • Animals
  • Apelin
  • Apelin Receptors
  • Carrier Proteins / metabolism*
  • Cell Differentiation / physiology*
  • Cell Line
  • Cells, Cultured
  • Embryo, Mammalian / metabolism
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism
  • Epidermal Growth Factor / genetics
  • Epidermal Growth Factor / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • GTP-Binding Proteins / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Myocardium / cytology
  • Myocardium / metabolism
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
  • Signal Transduction / physiology
  • Smad2 Protein / metabolism


  • Adipokines
  • Apelin
  • Apelin Receptors
  • Apln protein, mouse
  • Aplnr protein, mouse
  • Carrier Proteins
  • Intercellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • Receptors, G-Protein-Coupled
  • Smad2 Protein
  • Smad2 protein, mouse
  • Tdgf1 protein, mouse
  • Epidermal Growth Factor
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Extracellular Signal-Regulated MAP Kinases
  • GTP-Binding Proteins