Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors

Rutenberg, Joshua B.; Fischer, Andreas; Jia, Haibo; Gessler, Manfred; Zhong, Tao; Mercola, Mark

doi:10.1242/dev.02607

Cited by 149 publications

(148 citation statements)

References 82 publications

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“…Our present study shows that alterations of cardiomyocyte proliferative growth develop in grl mutant hearts. Additionally, Hairy-related transcription factors are involved in patterning the atrioventricular canal (28,29). These data suggest that cellular derangements in combination with patterning defects may underlie the morphologic alterations in these malformed hearts and potentially provide a cellular basis for some forms of congenital heart disease.…”

Section: Discussionmentioning

confidence: 93%

Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5

Jia

King²,

Chopra³

et al. 2007

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

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Embryonic organs attain their final dimensions through the generation of proper cell number and size, but the control mechanisms remain obscure. Here, we establish Gridlock (Grl), a Hairy-related basic helix-loop-helix (bHLH) transcription factor, as a negative regulator of cardiomyocyte proliferative growth in zebrafish embryos. Mutations in grl cause an increase in expression of a group of immediate-early growth genes, myocardial genes, and development of hyperplastic hearts. Conversely, cardiomyocytes with augmented Grl activity have diminished cell volume and fail to divide, resulting in a marked reduction in heart size. Both bHLH domain and carboxyl region are required for Grl negative control of myocardial proliferative growth. These Grl-induced cardiac effects are counterbalanced by the transcriptional activator Gata5 but not Gata4, which promotes cardiomyocyte expansion in the embryo. Biochemical analyses show that Grl forms a complex with Gata5 through the carboxyl region and can repress Gata5-mediated transcription via the bHLH domain. Hence, our studies suggest that Grl regulates embryonic heart growth via opposing Gata5, at least in part through their protein interactions in modulating gene expression.cardiomyocyte ͉ proliferation ͉ size control ͉ transcription T he embryonic heart grows through a combination of cardiomyocyte proliferation and an increase in cell mass due to the generation of myofibrillar arrays (1). Cardiac proliferation diminishes progressively after birth, and postmitotic hypertrophy in the adult heart provides most of the adaptive responses necessary to supply increased cardiac output (2). Despite recent progress that has been made in the regulation of postnatal cardiac hypertrophy, the mechanisms and pathways that control embryonic heart growth are poorly delineated. It is not known what molecular signals restrain cardiomyocyte proliferative growth in the embryonic heart. The GATA zinc-finger transcription factors promote myocardial differentiation and expansion. Among the three gata genes (gata4, gata5, and gata6) in zebrafish, gata5 plays the most prominent role in heart growth and development (3). Mutations in gata5 in zebrafish cause a reduction in expression of early and late myocardial genes and a decrease in cardiac progenitor cells and proliferative cardiomyocytes, resulting in small hearts. Forced gata5 expression in the zebrafish embryo increases heart size and occasionally produces ectopically beating myocardial tissue (4). The phenotype of zebrafish gata5 mutants closely resembles the cardiac phenotypes in gata4 mutant mice. Myocardium-restricted deletion of murine gata4 or gata4/gata6 double heterozygote causes a marked reduction in cardiomyocyte proliferation and results in hypoplastic hearts (5-7). Although it seems to be clear that certain levels of GATA activity are required to drive myocardial proliferative growth, opposing signals might also be necessary to constrain the excessive cardiac growth during development.grl encodes a hairy-related basic helix-loop-h...

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Section: Discussionmentioning

confidence: 93%

Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5

Jia

King²,

Chopra³

et al. 2007

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

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“…This might be explained by the downregulation of Hes1 and, more importantly, Hey2, an inhibitor of Bmp2 gene expression during AVC development. 33 Notch signaling thus may inhibit Bmp2 expression in the proepicardium thereby repressing its differentiation into muscle and establishing a posterior border for myocardial differentiation in the SV.…”

Section: Notch Signaling Inactivation Alters CI Differentiation By Inmentioning

confidence: 99%

Differential Notch Signaling in the Epicardium Is Required for Cardiac Inflow Development and Coronary Vessel Morphogenesis

Monte

Casanova

Guadix

et al. 2011

Circulation Research

146

134

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Rationale:The proepicardium is a transient structure comprising epicardial progenitor cells located at the posterior limit of the embryonic cardiac inflow. A network of signals regulates proepicardial cell fate and defines myocardial and nonmyocardial domains at the venous pole of the heart. During cardiac development, epicardial-derived cells also contribute to coronary vessel morphogenesis.Objective: To study Notch function during proepicardium development and coronary vessel formation in the mouse. Methods and Results:Using in situ hybridization, RT-PCR, and immunohistochemistry, we find that Notch pathway elements are differentially activated throughout the proepicardial-epicardial-coronary transition. Analysis of RBPJk-targeted embryos indicates that Notch ablation causes ectopic procardiogenic signaling in the proepicardium that in turn promotes myocardial differentiation in adjacent mesodermal progenitors, resulting in a premature muscularization of the sinus venosus horns. Epicardium-specific Notch1 ablation using a Wt1-Cre driver line disrupts coronary artery differentiation, reduces myocardium wall thickness and myocyte proliferation, and reduces Raldh2 expression. Ectopic Notch1 activation disrupts epicardium development and causes thinning of ventricular walls. T he early vertebrate heart consists of 2 tissue layers, the outer myocardium and the inner endocardium. At embryonic day (E)9.5 in mice, a third tissue, the epicardium, migrates to envelop the outer surface of the myocardium, actively participating in coronary vessels (CVs) morphogenesis and compact ventricular myocardium growth. 1 Epicardial progenitors are found in the proepicardium, a grape-like structure with characteristic protrusions (proepicardial villi). The proepicardium arises by E9.0 through local proliferation of the coelomic epithelium covering the septum transversum at the posterior limit (venous pole) of the heart. 2 The mesodermal progenitors underneath the proepicardium are often referred to as "posterior pericardial mesoderm," 3 a term that refers to topology rather than an embryological relation to the pericardial membranes. The venous pole of the heart provides the developing heart with myocardium, 4 a process that in the mouse finishes with the muscularization of the sinus horns. 5 The completion of the primitive epicardial epithelium covering the myocardium is followed by the appearance of the subepicardium, 1 an abundant extracellular matrix separating epicardium and myocardium. Concomitantly, the epicardium undergoes an epithelial-tomesenchymal transition (EMT) and populates the subepicardium with mesenchymal epicardial-derived cells (EPDCs), that contribute to the development of CVs and cardiac interstitium. 1 Proepicardial cells (proEPCs) can differentiate in vivo and in vitro into vascular/fibroblastic cell types or myocardium depending on the conditions. 3 A recent study proposed that proepicardial fate depends on the balance between Bmps and Fgfs signals, Bmps promoting myocardial differentiation and Fgfs f...

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“…It was first observed that Hey-induced EMT was required in the developing heart (26)(27)(28)(29). Subsequently, Hey proteins were found to be involved in tumor metastasis progression.…”

Section: The Roles Of Hey Proteins In Cancer Metastasismentioning

confidence: 99%

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

Liu

Sanders

Liang

et al. 2017

Molecular Cancer Therapeutics

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Hairy and Enhancer-of-split related with YRPW motif (Hey) transcription factors are important regulators of stem cell embryogenesis. Clinical relevance shows that they are also highly expressed in malignant carcinoma. Recent studies have highlighted functions for the Hey factors in tumor metastasis, the maintenance of cancer cell self-renewal, as well as proliferation and the promotion of tumor angiogenesis. Pathways that regulate Hey gene expression, such as Notch and TGFb signaling, are frequently aberrant in numerous cancers. In addition, Hey factors control downstream targets via recruitment of histone deacetylases (HDAC). Targeting these signaling pathways or HDACs may reverse tumor progression and provide clinical benefit for cancer patients. Thus, some small molecular inhibitors or monoclonal antibodies of each of these signaling pathways have been studied in clinical trials. This review focuses on the involvement of Hey proteins in malignant carcinoma progression and provides valuable therapeutic information for anticancer treatment.

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Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors

Cited by 149 publications

References 82 publications

Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5

Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5

Differential Notch Signaling in the Epicardium Is Required for Cardiac Inflow Development and Coronary Vessel Morphogenesis

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

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