Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development

High, Frances A.; Jain, Rajan; Stoller, Jason Z.; Antonucci, Nicole; Lü, Min; Loomes, Kathleen M.; Kaestner, Klaus H.; Pear, Warren S.; Epstein, Jonathan A.

doi:10.1172/jci38922

Cited by 129 publications

(187 citation statements)

References 55 publications

(65 reference statements)

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“…Interference with Notch signaling arrests cardiac development (6,(23)(24)(25). In accordance, MesP1-cre-induced mutation of RBPJ lox/lox (hereafter, "RBPJ mutant") reduced the size and compactness of the heart, as revealed by analyses of H&E-stained sections at embryonic day (E) 9.75 ( Fig.…”

Section: Resultsmentioning

confidence: 54%

“…Thus the up-regulated expression of such morphogens in double mutants also might contribute indirectly to the rescued development of nonmesoderm-derived cells (29). In previous analyses of mice that carried a conditional Jagged1 mutation or that expressed a dominant-negative Maml using Mef2c-cre also exhibit SHF morphogenesis affects and reduced Bmp and Fgf signaling (23). In contrast, in studies using Isl1-cre, elevated Wnt/ β-catenin signaling has been observed after conditional mutation of Notch1 but not RBPJ (24,25).…”

Section: Discussionmentioning

confidence: 98%

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Wnt/β-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells

Klaus

Müller²,

Schulz³

et al. 2012

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

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Progenitor cells of the first and second heart fields depend on cardiac-specific transcription factors for their differentiation. Using conditional mutagenesis of mouse embryos, we define the hierarchy of signaling events that controls the expression of cardiacspecific transcription factors during differentiation of cardiac progenitors at embryonic day 9.0. Wnt/β-catenin and Bmp act downstream of Notch/RBPJ at this developmental stage. Mutation of Axin2, the negative regulator of canonical Wnt signaling, enhances Wnt and Bmp4 signals and suffices to rescue the arrest of cardiac differentiation caused by loss of RBPJ. Using FACS enrichment of cardiac progenitors in RBPJ and RBPJ/Axin2 mutants, embryo cultures in the presence of the Bmp inhibitor Noggin, and by crossing a Bmp4 mutation into the RBPJ/Axin2 mutant background, we show that Wnt and Bmp4 signaling activate specific and nonoverlapping cardiac-specific genes in the cardiac progenitors: Nkx2-5, Isl1 and Baf60c are controlled by Wnt/β-catenin, and Gata4, SRF, and Mef2c are controlled by Bmp signaling. Our study contributes to the understanding of the regulatory hierarchies of cardiac progenitor differentiation and outflow tract development and has implications for understanding and modeling heart development.cardiogenesis | MesP1-cre | mesoderm patterning | canonical Wnt | progenitor differentiation in culture

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Section: Resultsmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 98%

Wnt/β-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells

Klaus

Müller²,

Schulz³

et al. 2012

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

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“…For example, reciprocal signaling between the second heart field and cardiac NCCs is required for proper patterning of the aortic arch arteries (Waldo et al, 2005). Deletion of Notch signaling specifically in the second heart field leads to altered NCC behavior, resulting in a decrease of NCC-derived tissue in the outflow tract and improper patterning of the arch arteries (High et al, 2009). Other NCCenriched miRNAs probably regulate similar pathways to coordinate the complex tissue-tissue interactions required to pattern the outflow tract and aortic arch arteries.…”

Section: Research Articlementioning

confidence: 99%

The neural crest-enriched microRNA miR-452 regulates epithelial-mesenchymal signaling in the first pharyngeal arch

et al. 2010

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SUMMARYNeural crest cells (NCCs) are a subset of multipotent, migratory stem cells that populate a large number of tissues during development and are important for craniofacial and cardiac morphogenesis. Although microRNAs (miRNAs) have emerged as important regulators of development and disease, little is known about their role in NCC development. Here, we show that loss of miRNA biogenesis by NCC-specific disruption of murine Dicer results in embryos lacking craniofacial cartilaginous structures, cardiac outflow tract septation and thymic and dorsal root ganglia development. Dicer mutant embryos had reduced expression of Dlx2, a transcriptional regulator of pharyngeal arch development, in the first pharyngeal arch (PA1). miR-452 was enriched in NCCs, was sufficient to rescue Dlx2 expression in Dicer mutant pharyngeal arches, and regulated non-cell-autonomous signaling involving Wnt5a, Shh and Fgf8 that converged on Dlx2 regulation in PA1. Correspondingly, knockdown of miR-452 in vivo decreased Dlx2 expression in the mandibular component of PA1, leading to craniofacial defects. These results suggest that posttranscriptional regulation by miRNAs is required for differentiation of NCC-derived tissues and that miR-452 is involved in epithelial-mesenchymal signaling in the pharyngeal arch.

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“…On binding with its ligand, a series of cleavage events release the Notch intracellular domain, which translocates to the nucleus and binds with its cofactors mastermind‐like protein and RBPJκ to regulate expression of target genes 14. Specifically, the Notch signaling family has been shown to play a critical role in cardiac OFT development because loss of the Notch signaling pathway, specifically in the SHF via a dominant‐negative truncated form of mastermind‐like protein or loss of Jagged1, results in a spectrum of OFT defects including aortic valve abnormalities 15. Furthermore, mutations in NOTCH2 and the Notch ligand JAGGED1 are responsible for Alagille syndrome, which is characterized by pulmonary stenosis, ventricular septal defects, coarctation of the aorta, and tetralogy of Fallot, among other developmental defects 16, 17.…”

Section: Introductionmentioning

confidence: 99%

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

Koenig

Bosse

Majumdar

et al. 2016

JAHA

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BackgroundCongenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal‐dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in Notch1‐haploinsufficient adult mice backcrossed into a Nos3‐null background.Methods and ResultsHere, we described the congenital cardiac abnormalities in Notch1 +/− ;Nos3 −/− embryos that led to ≈65% lethality by postnatal day 10. Although expected Mendelian ratios of Notch1 +/− ;Nos3 −/− embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of Notch1 +/− ;Nos3 −/− embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for Notch1 specifically in endothelial and endothelial‐derived cells in a Nos3‐null background and found that Notch1 fl/+;Tie2‐Cre +/− ;Nos3 −/− mice recapitulate the congenital cardiac phenotype of Notch1 +/− ;Nos3 −/− embryos.ConclusionsOur data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.

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Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development

Cited by 129 publications

References 55 publications

Wnt/β-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells

Wnt/β-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells

The neural crest-enriched microRNA miR-452 regulates epithelial-mesenchymal signaling in the first pharyngeal arch

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

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