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Published 27 October 2003. doi:10.1083/jcb.200303010
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© The Rockefeller University Press, 0021-9525/2003/10/303 $8.00
The Journal of Cell Biology, Volume 163, Number 2, 303-314

Article

 Nodal-dependent Cripto signaling promotes cardiomyogenesis and redirects the neural fate of embryonic stem cells

Silvia Parisi1, Daniela D'Andrea1, Carmine T. Lago1, Eileen D. Adamson2, M. Graziella Persico1 and Gabriella Minchiotti1

1 Institute of Genetics and Biophysics, "Adriano Buzzati-Traverso," Consiglio Nazionale delle Ricerche, 80131 Naples, Italy
2 Cancer Research Center, The Burnham Institute, La Jolla, CA 92037

Address correspondence to Gabriella Minchiotti, Institute of Genetics and Biophysics, "A. Buzzati-Traverso," CNR Via Pietro Castellino 111, 80131 Naples, Italy. Tel.: 39-081-6132354. Fax: 39-081-6132595. email: minchiot{at}iigb.na.cnr.it

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.

Key Words: Cripto; cardiomyocytes; neurons; differentiation; Nodal signaling

Abbreviations used in this paper: BMP, bone morphogenetic protein; ca, constitutively activated; Cerberus-S, Cerberus-Short; EB, embryoid body; ES, embryonic stem; HPRT, hypoxanthine phosphoribosyltransferase; MHC, myosin heavy chain; MLC, myosin light chain; wt, wild type.


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