BMP10 is essential for maintaining cardiac growth during murine cardiogenesis

Chen, Hanying; Shi, Shu Ping; Acosta, Lourdes; Li, Weiming; Lu, Jie; Bao, Shideng; Chen, Zhuang; Yang, Zhangping; Schneider, Michael; Chien, Kenneth R.; Conway, Simon J.; Yöder, Mervin C.; Haneline, Laura S.; Franco, Diego; Shou, Weinian

doi:10.1242/dev.01094

Cited by 451 publications

(423 citation statements)

References 46 publications

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“…To address the role of BMP9 and BMP10 in postnatal vascular remodeling, we used Bmp9-KO pups, which are fine and viable. They were injected at postnatal day 1 (P1) and P3 with a neutralizing anti-BMP10 antibody as previously described (8) because we could not use Bmp10-KO pups, which die at midgestation due to cardiac defects (9). We first analyzed transverse sections of the DA at P5 after hematoxylin and eosin (H&E) staining.…”

Section: Resultsmentioning

confidence: 99%

BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus

Levet

Ouarné

Ciais

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The transition to pulmonary respiration after birth requires rapid alterations in the structure of the mammalian cardiovascular system. One dramatic change that occurs is the closure of the ductus arteriosus (DA), an arterial connection in the fetus that directs blood flow away from the pulmonary circulation. Two members of the TGFβ family, bone morphogenetic protein 9 (BMP9) and BMP10, have been recently involved in postnatal angiogenesis, both being necessary for remodeling of newly formed microvascular beds. The aim of the present work was to study whether BMP9 and BMP10 could be involved in closure of the DA. We found that Bmp9 knockout in mice led to an imperfect closure of the DA. Further, addition of a neutralizing anti-BMP10 antibody at postnatal day 1 (P1) and P3 in these pups exacerbated the remodeling defect and led to a reopening of the DA at P4. Transmission electron microscopy images and immunofluorescence stainings suggested that this effect could be due to a defect in intimal cell differentiation from endothelial to mesenchymal cells, associated with a lack of extracellular matrix deposition within the center of the DA. This result was supported by the identification of the regulation by BMP9 and BMP10 of several genes known to be involved in this process. The involvement of these BMPs was further supported by human genomic data because we could define a critical region in chromosome 2 encoding eight genes including BMP10 that correlated with the presence of a patent DA. Together, these data establish roles for BMP9 and BMP10 in DA closure.T he ductus arteriosus (DA) is a large blood vessel whose obstruction is essential for the transition from fetal to neonatal circulation. It is a fetal arterial shunt connecting the pulmonary artery with the aortic arch. During fetal life, the DA directs deoxygenated blood away from the pulmonary circulation and toward the descending aorta, bypassing the nonventilated fetal lungs. After birth, the DA closes spontaneously within 1-3 h in small rodents or within 24-48 h in human newborns (1, 2). Although an open DA is required for fetal survival, the persistence of a patent DA (PDA) after birth is a major cause of morbidity and mortality, particularly in preterm neonates, leading to severe complications, including pulmonary hypertension, right ventricular dysfunction, postnatal infections, and respiratory failure. The incidence of PDA has been estimated to be one in 500 interm newborns and accounts for the majority of all cases of congenital heart disease in preterm newborns. It is currently believed that DA closure involves a two-step process (3, 4). The first, provisional closure, also called functional closure, occurs at birth and is accomplished by smooth muscle cell contraction and DA constriction. The second step, named anatomical closure, involves a profound remodeling of cells within the former DA lumen and permits permanent closure of the DA. Although several factors have been implicated in DA closure (oxygen tension, prostaglandin E2, laminin, growth ho...

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Section: Resultsmentioning

confidence: 99%

BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus

Levet

Ouarné

Ciais

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Trabeculation defect. Mouse cardiac trabeculation begins at E9.5 shortly after cardiac looping occurs (19). We examined and measured the trabeculae (trab) of E14.5 embryos ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Bmp10 is highly expressed in developing cardiac trabeculae (19). Loss of Bmp10 results in ventricular trabeculation defect due to decreased cardiomyocyte proliferation.…”

Section: Notch Signaling Pathway Was Perturbed In the Heart Of Zfp57mentioning

confidence: 99%

Maternal and zygotic Zfp57 modulate NOTCH signaling in cardiac development

Shamis

Cullen²,

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Zfp57 is a maternal–zygotic effect gene that maintains genomic imprinting. Here we report that Zfp57 mutants exhibited a variety of cardiac defects including atrial septal defect (ASD), ventricular septal defect (VSD), thin myocardium, and reduced trabeculation. Zfp57 maternal-zygotic mutant embryos displayed more severe phenotypes with higher penetrance than the zygotic ones. Cardiac progenitor cells exhibited proliferation and differentiation defects in Zfp57 mutants. ZFP57 is a master regulator of genomic imprinting, so the DNA methylation imprint was lost in embryonic heart without ZFP57. Interestingly, the presence of imprinted DLK1, a target of ZFP57, correlated with NOTCH1 activation in cardiac cells. These results suggest that ZFP57 may modulate NOTCH signaling during cardiac development. Indeed, loss of ZFP57 caused loss of NOTCH1 activation in embryonic heart with more severe loss observed in the maternal-zygotic mutant. Maternal and zygotic functions of Zfp57 appear to play redundant roles in NOTCH1 activation and cardiomyocyte differentiation. This serves as an example of a maternal effect that can influence mammalian organ development. It also links genomic imprinting to NOTCH signaling and particular developmental functions.

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“…Endocardial cells form a specialized endothelium that lines the inner (luminal) surface of the heart. The endocardium secretes factors, including neuregulin (Garratt, 2006) and BMP10 (Chen et al, 2004) among others, which instruct the underlying myocardium to proliferate and to organize into trabecular muscle. Epicardial cells form a layer on the outside of the heart beginning in mouse embryos around E9.5-E10.0 by means of the migration of precursors from the proepicardial organ (Manner, 1993;Sengbusch et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

PDGF‐A as an epicardial mitogen during heart development

Kang

et al. 2008

Developmental Dynamics

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In the developing heart, reciprocal interactions between the epicardium and myocardium drive further sublineage specification and ventricular chamber morphogenesis. Several observations suggest that the epicardium is a source of secreted factors that influence cardiomyocyte proliferation, and these factors may have other roles as well. However, the identity of these epicardial factors remains mostly unknown. We have identified platelet-derived growth factor-A (PDGF-A) as one of several mitogens expressed by the rat EMC epicardial cell line (epicardial mesothelial cells), by embryonic epicardium and myocardium during mouse heart development, and by adult epicardium. Expression of the cognate receptor gene Pdgfra was detected in the epicardium, although a low level of expression in myocardium could not be ruled out. To address the potential role of PDGF signaling in heart development, we mutated both PDGF receptor genes in the myocardial and mesodermal compartments of the heart; however, this did not result in an observable cardiac phenotype. This finding suggests that mesodermal PDGF signaling is not essential in heart development, although its role may be redundant with other signaling pathways. Indeed, our results demonstrate the presence of additional mitogens that may have such an overlapping role. Developmental Dynamics 237:692-701, 2008.

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BMP10 is essential for maintaining cardiac growth during murine cardiogenesis

Cited by 451 publications

References 46 publications

BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus

BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus

Maternal and zygotic Zfp57 modulate NOTCH signaling in cardiac development

PDGF‐A as an epicardial mitogen during heart development

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