Bmp Signaling Exerts Opposite Effects on Cardiac Differentiation

Abstract

Rationale The importance for Bmp signaling during embryonic stem cell differentiation into myocardial cells has been recognized. The question when and where Bmp signaling in vivo regulates myocardial differentiation has remained largely unanswered. Objective To identify when and where Bmp signaling regulates cardiogenic differentiation. Methods and Results Here we have observed that in zebrafish embryos, Bmp signaling is active in cardiac progenitor cells prior to their differentiation into cardiomyocytes. Bmp signaling is continuously required during somitogenesis within the anterior lateral plate mesoderm to induce myocardial differentiation. Surprisingly, Bmp signaling is actively repressed in differentiating myocardial cells. We identified the inhibitory Smad6a, which is expressed in the cardiac tissue, to be required to inhibit Bmp signaling and thereby promote expansion of the ventricular myocardium. Conclusion Bmp signaling exerts opposing effects on myocardial differentiation in the embryo by promoting as well as inhibiting cardiac growth.

Glypican4 promotes cardiac specification and differentiation by attenuating canonical Wnt and Bmp signaling

“…Indeed, BMP signaling and Wnt signaling have distinct roles in regulating SHF specification and differentiation in the anterior LPM of mouse embryos (Klaus et al, 2012). Our observation that Glypican4 is required to attenuate BMP signaling to allow proper differentiation of myl7 + cardiomyocytes is consistent with a model in which BMP signaling is required to induce nkx2.5 expression in the anterior LPM, but that BMP signaling in cardiac progenitor cells needs to be downregulated to allow efficient cardiomyocyte differentiation (Hao et al, 2008;de Pater et al, 2012;Cai et al, 2013). Glypicans have been implicated in the control of TGF-β/Bmp activity (Jackson et al, 1997;Paine-Saunders et al, 2000;Li et al, 2004).…”

“…To test this hypothesis, we crossed the Tg(hsp70:nog), in which the Bmp antagonist Noggin3 is induced upon heat shock, into the kny/gpc4 mutant line. Induction of Noggin3 at 16 hpf in wild-type embryos results in a moderate reduction in atrial cardiomyocytes, whereas the number of ventricular cardiomyocytes remains unaffected, probably reflecting the temporal differences in the specification of atrial versus ventricular progenitor cells (de Pater et al, 2012). Corroborating our hypothesis, induction of Noggin3 at 16 hpf in kny/gpc4 mutants resulted in a modest but significant increase in myl7 + ventricular cardiomyocytes (Fig.…”

“…HSPGs such as glypicans can interact with extracellular BMP, and BMP signaling is required for the induction of nkx2.5 expression, whereas inhibition of BMP signaling promotes the differentiation of cardiac progenitor cells (Schultheiss et al, 1997;Fujise et al, 2003;Belenkaya et al, 2004;Andrée et al, 1998;Schlange et al, 2000;Yuasa et al, 2005;Matsui et al, 2005;Taha et al, 2007;Hao et al, 2008;de Pater et al, 2012;Cai et al, 2013). We analyzed Bmp signaling activity in the LPM, using a Bmp reporter line Tg(bre:gfp) crossed into the kny/gpc4 mutant.…”

“…Nevertheless, several signaling pathways (e.g. FGF, Hh and TGF-β) have been identified that regulate the late differentiation of progenitors at the arterial pole in zebrafish (de Pater et al, 2009(de Pater et al, , 2012Hami et al, 2011;Zhou et al, 2011).…”

Genetics and Genetic Testing in Congenital Heart Disease

“…The impact of a particular signal can vary dramatically as development proceeds, operating positively at one stage and negatively at another. For example, Bmp signaling is required to induce differentiation of early cardiac progenitors, but is inhibited at later stages by Smad6a to permit Tbx2-and Tbx20-mediated chamber development 27 .…”