Cardiomyocyte Differentiation through BMP Receptors
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Cardiomyocyte Differentiation through BMP Receptors

BMP (Bone Morphogenetic Protein) Receptors are essential, beyond the egg cylinder stage, for myocyte-dependent functions and signals in cardiac organogenesis. ALK3 (Activin Receptor-Like Kinase-3) is specifically required at mid-gestation for normal development of the trabeculae, compact myocardium, interventricular septum and endocardial cushion. The invariable defects in myocardium results from congenital deletion of ALK3 and this provide strong support for its assessment as a candidate gene in human congenital heart disease. BMPs like BMP2, BMP4 and BMP5, BMP7, BMP10, bind to Serine/threonine kinase receptors, Type-I (ALK3 and ALK6) and Type-II, BMPR2 (Bone Morphogenetic Protein Receptor Type-II), respectively, and form a heteromeric signaling complex acting in series (Ref.1). In the presence of ligand, the Type-II receptor phosphorylates the Type-I receptors, which activate signaling by intracellular effectors including SMAD (Sma and MAD (Mothers Against Decapentaplegic) Related Protein) transcription factors. ALK3 is ubiquitous throughout development, whereas ALK6 is absent from the heart at mid-gestation. ALK3 and BMPR2 are each essential for gastrulation and mesoderm formation. Therefore the existence of human mutations in receptors for BMPs is a cause of clinical cardiovascular disorders including pulmonary hypertension and hereditary hemorrhagic telangiectasia. The loss of ALK3 in mid-gestation myocardium quickly leads to multiple cardiac defects, which coincide with the distribution of BMPs in the heart; BMP2 and BMP4 adjacent to the AV (Atrioventricular) cushion, BMP5 and BMP7 more homogenously and BMP10 in the trabeculae (Ref.2).

TAK1 (Transforming Growth Factor-Beta-Activated Kinase-1) and cardiac transcription factors like NKX2.5 (NK2 Transcription Factor Related Locus-5) and GATA4 (GATA Binding Protein-4) plays pivotal role in the cardiogenic BMP signaling pathway. TAK1 is activated by BMPs and also mediates the activity of BMPs. Further the cross talk between the SMAD pathway and the TAK1 pathway induce differentiation of cardiac precursor cells. Among the members of SMADs, SMAD1, SMAD5 and SMAD8 transduce signals from BMPs specifically, while SMAD4 is a general partner of ligand-specific SMADs. Co-overexpression of SMAD1 and SMAD4 induce differentiation of cardiac precursor cells into cardiomyocytes and overexpression of SMAD6, an inhibitory SMAD blocks the signal transduction and inhibits differentiation of the cardiac precursor cells into cardiomyocytes (Ref.2 & 3). SMAD6 is an inhibitory SMAD that is induced by BMPs and interferes with BMP signaling. The PBE (Proximal BMP-Responsive Element) in the SMAD6 promoter is important for the transcriptional activation by BMPs and contains a 28-base pair GC-rich sequence including four overlapping copies of the GCCGnCGC-like motif. BMPs and BMP receptors induce transcriptional activation of SMAD1 or SMAD5. It has been reported recently that expression of SMAD6 itself is regulated by BMP-activated SMAD1 or SMAD5 on the SMAD6 promoter. However further studies are necessary to elucidate the role of SMADs in vertebrate cardiogenesis (Ref.4). Initially, BMPs (especially BMP2 and/or BMP4) transactivate the expression of two major cardiac-specific transcription factors, NKX2.5 and GATA4. This transactivation is mediated by TAK1. Subsequently, NKX2.5 and GATA4 induce differentiation into cardiomyocytes cooperatively with unknown factor(s) induced by DMSO (Dimethyl sulfoxide). The unknown factor(s) induced by DMSO is also required for this step, because neither expression of NKX2.5 and GATA4 nor subsequent terminal differentiation into cardiomyocytes can be induced in the absence of DMSO. Although some cardiac-specific genes, such as MEF2C (MADS Box Transcription Enhancer Factor-2 Polypeptide-C) and MLC2v (Ventricular Myosin Light Chain Type-2), are upregulated by NKX2.5 and GATA4 alone, differentiation into beating cardiomyocytes requires the cooperative effects of both NKX2.5 and GATA4. MLC2v and MEF2C are positively regulated by NKX2.5. MEF2C binds to the AT-rich element in regulatory regions of numerous muscle-specific genes. GATA4 binds to the WGATAR motif in promoter regions of cardiac- or gut-specific genes. Both MEF2C and GATA4 are expressed simultaneously in the precardiac mesoderm along with NKX2.5. Thus, BMPs and downstream transcription factors are the central molecules of this regulatory network controlling cardiac differentiation as well as the DMSO-inducible factors. The identification of signals induced by DMSO in this system will provide new insights into the regulatory mechanisms of differentiation of cardiac precursor cells (Ref.3).

ATF2 (Activating Transcription Factor-2) stimulates the Beta-MHC (Beta-Myosin Heavy Chain) promoter activity synergistically with SMAD1, SMAD4 and TAK1 and promotes terminal cardiomyocyte differentiation. ATF2 binds directly to hetero-oligomers of SMADs and is phosphorylated by TGF-Beta signaling via TAK1 and p38 . ATF2-induced transactivation of Beta-MHC gene depends on both the SMAD and the TAK1 pathways (Ref.5). Single amino acid changes in Beta-MHC result in abnormal actomyosin interactions, confirming the primary role of missense mutations in Beta-MHC gene in the etiology of hypertrophic cardiomyopathy. Apart from stimulating Beta-MHC, ATF2 also plays a pivotal role in transactivation of some cardiac-specific genes like NPPA (Natriuretic Peptide Precursor-A) and NPPB (Natriuretic Peptide Precursor-B). The hetero-oligomer of SMAD3 and SMAD4 bind directly to ATF2 through the MH1 (MAD Homology-1) region of SMAD3 and SMAD4 and the bZIP region of ATF2 and enhance the transactivating capacity of ATF2. NPPB is the major heart secretory product that is also accepted as clinical markers of the diseased heart and it is also controlled by GATA factors (Ref.6 & 7). In humans, congenital heart defects occur with a prevalence of at least one percent in newborns and are even more common in death before term. Most frequent are defects in septation and the cardiac valves and few single-gene etiologies are known. The invariable defects in myocardium and AV cushion resulting from conditional deletion of BMP receptors provide strong support for their assessment as candidate genes in human congenital heart diseases (Ref.1).