Functional BMP receptor in endocardial cells is required in atrioventricular cushion mesenchymal cell formation in chick

Abstract

Transformation of atrioventricular (AV) canal endocardium into invasive mesenchyme correlates spatially and temporally with the expression of bone morphogenetic protein (BMP)-2 in the AV myocardium. We revealed the presence of mRNA of Type I BMP receptors, BMPR-1A (ALK3), BMPR-1B (ALK6) and ALK2 in chick AV endocardium at stage-14(-), the onset of epithelial to mesenchymal transformation (EMT), by RT-PCR and localized BMPR-1B mRNA in the endocardium by in situ hybridization. To circumvent the functional redundancies among the Type I BMP receptors, we applied dominant-negative (dn) BMPR-1B-viruses to chick AV explants and whole-chick embryo cultures to specifically block BMP signaling in AV endocardium during EMT. dnBMPR-1B-virus infection of AV endocardial cells abolished BMP-2-supported AV endocardial EMT. Conversely, caBMPR-1B-virus infection promoted AV endocardial EMT in the absence of AV myocardium. Moreover, dnBMPR-1B-virus treatments significantly reduced myocardially supported EMT in AV endocardial-myocardial co-culture. AV cushion mesenchymal cell markers, alpha-smooth muscle actin (SMA), and TGFbeta3 in the endocardial cells were promoted by caBMPR-1B and reduced by dnBMPR-1B infection. Microinjection of the virus into the cardiac jelly in the AV canal at stage-13 in vivo (ovo) revealed that the dnBMPR-1B-virus-infected cells remained in the endocardial epithelium, whereas caBMPR-1B-infected cells invaded deep into the cushions. These results provide evidence that BMP signaling through the AV endocardium is required for the EMT and the activation of the BMP receptor in the endocardium can promote AV EMT in the chick.

Accessory Atrioventricular Myocardial Connections in the Developing Human Heart

“…8,16 The development of this isolating structure involves several processes in which the endocardial cushions that line the luminal side of the primitive AV canal, together with the inward migration of the epicardially located AV sulcus tissue, play an important role. [17][18][19] Recently, it has been shown in more detail that a combination of bone morphogenetic protein signaling, 20,21 periostin (an osteoblast-specific factor), 22 and epicardiumderived cells that enter the heart at the AV sulcus play a key role in this process. 23,24 The cause of APs has not been elucidated.…”

Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart

“…The deletion of the BMP type 1A receptor in the endocardium also resulted in failed cushion formation, indicating that BMP signals directly to cushion-forming endocardium to induce epithelial-mesenchyme transition (27). Transformation of atrioventricular (AV) canal endocardium into invasive mesenchyme correlates spatially and temporally with the expression of BMPs in the atrioventricular myocardium crucial for the induction of Postn (28). Kühn et al (29) showed that periostin-induced cardiomyocyte cell-cycle reentry and mitosis, whereas periostin expression was associated with improved ventricular remodeling and myocardial function (30).…”

BMP4 induces an epithelial–mesenchymal transition-like response in adult airway epithelial cells

“…Both are critical to a variety of developmental processes including EMT aspects of morphogenesis (Chen et al 2004). BMP4 drives early mesoderm formation (Winnier et al 1995) while BMP2 is required for EMT during heart morphogenesis (Okagawa et al 2007). Homozygous deletions of BMP2 and BMP4 in mice are embryonic lethal due to abnormal heart development and a failure of mesoderm formation, respectively (Winnier et al 1995;Zhang and Evans 1996).…”