Inhibition of Wnt activity induces heart formation from posterior mesoderm

Abstract

In the chick, heart mesoderm is induced by signals from the anterior endoderm. Although BMP-2 is expressed in the anterior endoderm, BMP activity is necessary but not sufficient for heart formation. Previous work from our lab has suggested that one or more additional factors from anterior endoderm are required. Crescent is a Frizzled-related protein that inhibits Wnt-8c and is expressed in anterior endoderm during gastrulation. At the same stages, expression of Wnt-3a and Wnt-8c is restricted to the primitive streak and posterior lateral plate, and is absent from the anterior region where crescent is expressed. Posterior lateral plate mesoderm normally forms blood, but coculture of this tissue with anterior endoderm or infection with RCAS-crescent induces formation of beating heart muscle and represses formation of blood. Dkk-1, a Wnt inhibitor of a different protein family, similarly induces heart-specific gene expression in posterior lateral plate mesoderm. Furthermore, we have found that ectopic Wnt signals can repress heart formation from anterior mesoderm in vitro and in vivo and that forced expression of either Wnt-3a or Wnt-8c can promote development of primitive erythrocytes from the precardiac region. We conclude that inhibition of Wnt signaling promotes heart formation in the anterior lateral mesoderm, whereas active Wnt signaling in the posterior lateral mesoderm promotes blood development. We propose a model in which two orthogonal gradients, one of Wnt activity along the anterior-posterior axis and the other of BMP signals along the dorsal-ventral axis, intersect in the heart-forming region to induce cardiogenesis in a region of high BMP and low Wnt activity.

Function and biological roles of the Dickkopf family of Wnt modulators

“…Dkk1 and crescent (a Wnt inhibitor of the sFRP family) are able to induce myocardial tissue formation from putative noncardiogenic mesodermal tissue (Marvin et al, 2001;Schneider and Mercola, 2001). While this supports the idea that Wnt inhibition is required for formation of yet another organ of anterior origin, Dkk1 may not be essential for this process, or act redundantly with other Wnt inhibitors, since Dkk1 mutant mice have apparently normal hearts.…”

Early temporal‐specific responses and differential sensitivity to lithium and Wnt‐3A exposure during heart development

“…The antagonist Dkk1 interacts with LRP5/6, which in turn acts as high affinity antagonists to the frizzled receptors (Bafico et al, 2001;Mao et al, 2001). Based upon previous studies, canonical Wnt signaling is important for cardiac cell differentiation (Linask, 1992a;Linask et al, 1997;Marvin et al, 2001;Schneider and Mercola, 2001;Tzahor and Lassar, 2001). The lithium/Wnt-3A experiments reported here show that it is an early canonical Wnt-mediated anteroposterior (AP) signaling wave that is necessary and coordinated with the other specified factors to define cardiac cell fate and the boundaries of the cardiac compartment within the mesoderm.…”

In vitro organogenesis from undifferentiated cells in Xenopus

“…Thus, screening with these in vitro-induced hearts has contributed new knowledge as to when and how the components of the hyaluronan matrix function in cardiogenesis. These systems also permit more detailed analyses of the roles of Wnt signaling (Marvin et al, 2001;Schneider and Mercola, 2001;Tzahor and Lassar, 2001) and transcription factors, such as Nkx2.5 (Durocher et al, 1997;Reecy et al, 1999) and GATA4 (Grepin et al, 1995(Grepin et al, , 1997Jiang et al, 1999) in cardiogenesis. In the recent study, we examined a comprehensive set of cardiogenesis-related genes using an in vitro Xenopus-based system and microarrays.…”