Developmental stage-specific biphasic roles of Wnt/β-catenin signaling in cardiomyogenesis and hematopoiesis

doi:10.1073/pnas.0605768103

Developmental stage-specific biphasic roles of Wnt/β-catenin signaling in cardiomyogenesis and hematopoiesis

*Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;
^†Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan; and
^‡Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan

Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved October 23, 2006 (received for review July 10, 2006)

Abstract

Although Wingless (Wg)/Wnt signaling has been implicated in heart development of multiple organisms, conflicting results have been reported regarding the role of Wnt/β-catenin pathway in cardiac myogenesis: Wg/armadillo signaling promotes heart development in Drosophila, whereas activation of Wnt/β-catenin signaling inhibits heart formation in avians and amphibians. Using an in vitro system of mouse ES cell differentiation into cardiomyocytes, we show here that Wnt/β-catenin signaling exhibits developmental stage-specific, biphasic, and antagonistic effects on cardiomyogenesis and hematopoiesis/vasculogenesis. Activation of the Wnt/β-catenin pathway in the early phase during embryoid body (EB) formation enhances ES cell differentiation into cardiomyocytes while suppressing the differentiation into hematopoietic and vascular cell lineages. In contrast, activation of Wnt/β-catenin signaling in the late phase after EB formation inhibits cardiomyocyte differentiation and enhances the expression of hematopoietic/vascular marker genes through suppression of bone morphogenetic protein signaling. Thus, Wnt/β-catenin signaling exhibits biphasic and antagonistic effects on cardiomyogenesis and hematopoiesis/vasculogenesis, depending on the stage of development.

cardiogenesis

Footnotes

^§To whom correspondence should be addressed. E-mail: komuro-tky{at}umin.ac.jp
Author contributions: A.T.N., I.S., and I.K. designed research; A.T.N. performed research; H.A., K.H., T.M., and A.K. contributed new reagents/analytic tools; A.T.N. analyzed data; and A.T.N., I.S., and I.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0605768103/DC1.
Abbreviations:

BMP,

bone morphogenetic protein;

cTnT,

cardiac troponin T;

Dkk-1,

Dickkopf-1;

EB,

embryoid body;

Fz8/Fc,

Frizzled-8/Fc chimeric protein;

Wg,

Wingless;

DM,

differentiation medium.