The involvement of non-canonical Wnt signaling in early cardiomorphogenesis
Final Report Abstract
Glypicans are heparan sulphate proteoglycans attached to the cell membrane by a glycosylphosphatidylinositol (GPI)-anchor and interact with various extracellular growth factors and receptors. The Drosophila division abnormal delayed (dally) was the first glypican loss-of-function mutant described displaying disrupted cell divisions in the eye and morphological defects in the wing. In human, as in most vertebrates, 6 glypican coding genes have been identified (GPC1-6) and mutations in several glypican genes cause multiple malformations including congenital heart defects. To better understand the role of glypicans during heart development we studied the zebrafish knypek mutant which is deficient for Gpc4. Our results demonstrate that knypek/gpc4 mutant embryos display severe cardiac defects, most apparent by a strong reduction in cardiomyocyte numbers. Cell-tracing experiments using photoconvertable fluorescent proteins and genetic labeling demonstrate that Gpc4 “Knypek” is required for cardiomyocyte differentiation of cardiac progenitor cells that are derived from the so called second heart field. Mechanistically we show that canonical Wnt signaling is up regulated in knypek/gpc4 embryos and that inhibiting canonical Wnt signaling in knypek/gpc4 embryos by overexpression of the Wnt inhibitor Dkk1 restores normal cardiomyocyte numbers. Moreover, we observed enhanced Bmp signaling in the cardiac field of knypek/gpc4 mutants. Genetic inhibition of Bmp signaling rescued the cardiomyocyte differentiation defect in knypek/gpc4 embryos. Therefore we conclude that Gpc4 is required to attenuate both canonical Wnt and Bmp signaling in the cardiac field to allow cardiac progenitor cells to differentiate into cardiomyocytes, providing a possible explanation for how congenital heart defects arise in glypican deficient patients.
Publications
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(2012). BMP signaling exerts opposite effects on cardiac differentiation. Circ Res.110(4): 578-87
de Pater, Emma; Ciampricotti, Metamia; Priller, Florian; Veerkamp, Justus; Strate, Ina; Smith, Kelly; Lagendijk, Anne Karine; Schilling, Thomas F.; Herzog, Wiebke; Abdelilah-Seyfried, Salim; Hammerschmidt, Matthias & Bakkers, Jeroen
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(2012).Identification and regulation of a molecular module for bleb-based cell motility. Dev.Cell 23(1):210-8
Goudarzi, Mehdi; Banisch, Torsten U.; Mobin, Mehrpouya B.; Maghelli, Nicola; Tarbashevich, Katsiaryna; Strate, Ina; van den Berg, Jana; Blaser, Heiko; Bandemer, Sabine; Paluch, Ewa; Bakkers, Jeroen; Tolić-Nørrelykke, Iva M. & Raz, Erez
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(2013) On the robustness of germ cell migration and miRNA-mediated regulation of chemokine signaling. Nature Genetics, 45(11):1264-5
Goudarzi M, Strate I, Lagendijk AK, Bakkers J, Raz E
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Glypican4 promotes cardiac specification and differentiation by attenuating canonical Wnt and Bmp signaling. Development 2015 142: 1767-1776
Strate, Ina; Tessadori, Federico & Bakkers, Jeroen
