Wnt antagonism initiates cardiogenesis in Xenopus laevis

Abstract

Heart induction in Xenopus occurs in paired regions of the dorsoanterior mesoderm in response to signals from the Spemann organizer and underlying dorsoanterior endoderm. These tissues together are sufficient to induce heart formation in noncardiogenic ventral marginal zone mesoderm. Similarly, in avians the underlying definitive endoderm induces cardiogenesis in precardiac mesoderm. Heart-inducing factors in amphibians are not known, and although certain BMPs and FGFs can mimic aspects of cardiogenesis in avians, neither can induce the full range of activities elicited by the inducing tissues. Here we report that the Wnt antagonists Dkk-1 and Crescent can induce heart formation in explants of ventral marginal zone mesoderm. Other Wnt antagonists, including the frizzled domain-containing proteins Frzb and Szl, lacked this activity. Unlike Wnt antagonism, inhibition of BMP signaling did not promote cardiogenesis. Ectopic expression of GSK3␤, which inhibits ␤-catenin-mediated Wnt signaling, also induced cardiogenesis in ventral mesoderm. Analysis of Wnt proteins expressed during gastrulation revealed that Wnt3A and Wnt8, but not Wnt5A or Wnt11, inhibited endogenous heart induction. These results indicate that diffusion of Dkk-1 and Crescent from the organizer initiate cardiogenesis in adjacent mesoderm by establishing a zone of low Wnt3A and Wnt8 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.…”

In vitro organogenesis from undifferentiated cells in Xenopus

“…In Xenopus, cardiogenesis is initiated by the combined action of Wnt antagonists from the Spemann organizer and several endodermal factors (Nascone and Mercola, 1995;Shi et al, 2000;Schneider and Mercola, 2001). Cardiac progenitor cells are formed bilaterally on mesodermal tissues adjacent to the Spemann organizer during the early gastrula stages.…”

“…This structure comprises approximately 1,000 cells, and is known to be capable of inducing the differentiation of myocardial cells by activating activin (Logan and Mohun, 1993;Ariizumi et al, 1996) and causing the overexpression of proteins, such as GATA4 (Latinkic et al, 2003). Moreover, explants of the noncardiogenic ventral marginal zone (VMZ) formed beating structures through the overexpression of Xwnt11, crescent or dkk1 (Schneider and Mercola, 2001;Pandur et al, 2002). However, in all these investigations, the induction rate for myocardial cells was not high, and the induced tissues did not structurally resemble the heart.…”

“…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.…”

Stem cells and the formation of the myocardium in the vertebrate embryo

“…5). These cardiogenic enhancers include several members of the BMP and FGF growth factor families Ladd et al, 1998;Alsan and Schultheiss, 2002) and three distinct modulators of WNT signal transduction: WNT11, Dkk1, and crescent (Eisenberg and Eisenberg, 1999;Marvin et al, 2001;Schneider and Mercola, 2001;Pandur et al, 2002). The cardiac-promoting activities of these molecules appear to correlate with their involvement in normal cardiogenesis in the embryo.…”