Nodal-dependent Cripto signaling promotes cardiomyogenesis and redirects the neural fate of embryonic stem cells.
The molecular mechanisms controlling inductive events leading to the specification and terminal differentiation of cardiomyocytes are still largely unknown. We have investigated the role of Cripto, an EGF-CFC factor, in the earliest stages of cardiomyogenesis. We find that both the timing of initiation and the duration of Cripto signaling are crucial for priming differentiation of embryonic stem (ES) cells into cardiomyocytes, indicating that Cripto acts early to determine the cardiac fate. Furthermore, we show that failure to activate Cripto signaling in this early window of time results in a direct conversion of ES cells into a neural fate. Moreover, the induction of Cripto activates the Smad2 pathway, and overexpression of activated forms of type I receptor ActRIB compensates for the lack of Cripto signaling in promoting cardiomyogenesis. Finally, we show that Nodal antagonists inhibit Cripto-regulated cardiomyocyte induction and differentiation in ES cells. All together our findings provide evidence for a novel role of the Nodal/Cripto/Alk4 pathway in this process.
Institute of Genetics and Biophysics, "Adriano Buzzati-Traverso," Consiglio Naziolale delle Ricerche, Naples, Italy.
Silvia
S
Parisi
Daniela
D
D'Andrea
Carmine T
CT
Lago
Eileen D
ED
Adamson
M Graziella
MG
Persico
Gabriella
G
Minchiotti
D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000378:metabolism; D000595:Amino Acid Sequence; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004627:Embryonic Induction; D004815:Epidermal Growth Factor; D058851:GPI-Linked Proteins; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D055457:Nodal Protein; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics; D051899:Smad2 Protein; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D029867:Xenopus Proteins
D004268:DNA-Binding Proteins; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C526007:NODAL protein, human; D009363:Neoplasm Proteins; D055457:Nodal Protein; D011506:Proteins; D011994:Recombinant Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C070636:TDGF1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C100866:cer1 protein, Xenopus; D004815:Epidermal Growth Factor; C425423:ACVR1 protein, human; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II