Bmp Signaling Regulates Myocardial Differentiation from Cardiac Progenitors Through a MicroRNA-Mediated Mechanism

Wang, Jun; Greene, Stephanie; Bonilla-Claudio, Margarita; Tao, Ye; Zhang, Jue; Bai, Yan; Huang, Zheng; Black, Brian L.; Wang, Fen; Martin, James F.

doi:10.1016/j.devcel.2010.10.022

Cited by 166 publications

(174 citation statements)

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“…Several effects of Bmp signaling in cardiomyocyte differentiation have been described previously High Bmp activity is required for Gata4 expression and for the initiation of Nkx2-5 expression at E8, but our data indicate that at E9 the maintenance of Nkx2-5 no longer is Bmp dependent (9,13,14). Furthermore, miRNA-dependent fine-tuning of Isl1 also is regulated by Bmp signals (12). Several laboratories have identified cardiac progenitor and stem cells by using various protocols for sorting and culture (27).…”

Section: Discussionmentioning

confidence: 41%

“…During predifferentiation of cardiac progenitors into cardioblasts, these transcription factors induce the expression of Mef2c and Hand1/2 and also early cardiac muscle-specific genes, e.g., the genes that encode cardiac actin and myosin light chain 2a (8)(9)(10). In the differentiation phase, down-regulation of Isl1 and interaction of Mef2c/Hand1/2 with the core complex induce the expression of cardiac muscle-specific genes for structural proteins such as troponin T2 and myosin heavy chains (11,12).…”

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confidence: 99%

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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: Discussionmentioning

confidence: 41%

mentioning

confidence: 99%

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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confidence: 99%

“…S1A) (11, 12). Germ-line miR-17-92 loss-of-function results in heart defects including ventricular septal defects that result from abnormal differentiation of second heart field cardiac progenitors (13,14).Paired-like homeodomain transcription factor 2 (Pitx2) is the gene in closest proximity to the 4q25 SNV that has biologic relevance for AF (5). Pitx2 is expressed on the left side of multiple organ primordia and mature organs including the heart.…”

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confidence: 99%

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Wang¹,

Bai

Li³

et al. 2014

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

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The molecular mechanisms underlying atrial fibrillation, the most common sustained cardiac arrhythmia, remain poorly understood. Genome-wide association studies uncovered a major atrial fibrillation susceptibility locus on human chromosome 4q25 in close proximity to the paired-like homeodomain transcription factor 2 (Pitx2) homeobox gene. Pitx2, a target of the left-sided Nodal signaling pathway that initiates early in development, represses the sinoatrial node program and pacemaker activity on the left side. To address the mechanisms underlying this repressive activity, we hypothesized that Pitx2 regulates microRNAs (miRs) to repress the sinoatrial node genetic program. MiRs are small noncoding RNAs that regulate gene expression posttranscriptionally. Using an integrated genomic approach, we discovered that Pitx2 positively regulates miR-17-92 and miR-106b-25. Intracardiac electrical stimulation revealed that both miR-17-92 and miR-106b-25 deficient mice exhibit pacing-induced atrial fibrillation. Furthermore electrocardiogram telemetry revealed that mice with miR-17-92 cardiac-specific inactivation develop prolonged PR intervals whereas mice with miR-17-92 cardiac-specific inactivation and miR-106b-25 heterozygosity develop sinoatrial node dysfunction. Both arrhythmias are risk factors for atrial fibrillation in humans. Importantly, miR-17-92 and miR-106b-25 directly repress genes, such as Shox2 and Tbx3, that are required for sinoatrial node development. Together, to our knowledge, these findings provide the first genetic evidence for an miR loss-of-function that increases atrial fibrillation susceptibility. irregular heart rate | single nucleotide variant | mouse genetics A trial fibrillation (AF), the most common arrhythmia in adult patients, increases in prevalence with age to almost 5% of the population over 65. Patients with AF have an increased risk of stroke, dementia, and heart failure (1). Electrical impulses that are critical for a coordinated, physiologic heartbeat originate in the sinoatrial node (SAN). In AF, abnormal fibrillatory atrial impulses override normal SAN function, with resultant irregular conduction to the ventricles. Many cases of ectopic electrical activity originate in the pulmonary vein (2). Other sites of ectopy include the left atrial posterior wall, superior vena cava, interatrial septum, crista terminalis, and coronary sinus myocardium (3, 4).Multiple approaches have been used to uncover genes that may contribute to the AF phenotype in adult patients. A seminal genome-wide association study (GWAS), subsequently replicated by multiple studies, uncovered a single nucleotide variant (SNV) on human 4q25 that was strongly associated with familial AF (5). Patients with the 4q25 variant exhibited early onset AF that was independent from other risk factors such as hypertension and diabetes, suggesting a novel biologic mechanism involving genes located on chromosome 4q25. The presence of the 4q25 SNV also had prognostic value because patients with the SNV are prone to cardioembolic str...

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“…second heart field [35]. The depletion of miR-17/92 cluster in mice has been shown to cause death after birth due to ventricular septal defects and lung hypoplasia, while its overexpression causes repressed fibronectin expression with subsequent cellular defects and overall delayed organ growth [36].…”

Section: Mirs and Cardiac Developmentmentioning

confidence: 99%

Interactions between microRNAs and long non-coding RNAs in cardiac development and repair

Rotini

Martínez‐Sarrà

Pozzo

et al. 2018

Pharmacological Research

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Please cite this article as: Rotini Alessio, Martínez-Sarrà Ester, Pozzo Enrico, Sampaolesi Maurilio.Interactions between microRNAs and long noncoding RNAs in cardiac development and repair.Pharmacological Research http://dx.doi.org/10.1016/j.phrs. 2017.05.029 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Graphical abstract.The regulation of cardiac development by miRs and lncRNAs, and their interaction in pathological setting. AbstractNon-coding RNAs (ncRNAs) are emerging players in muscle regulation. Based on their length and differences in molecular structure, ncRNAs are subdivided into several categories including small interfering RNAs, stable non-coding RNAs, microRNAs (miRs), long non-coding RNAs (lncRNAs), and circular RNAs. miRs and lncRNAs are able to post-transcriptionally regulate many genes and bring into play several traits simultaneously due to a myriad of different targets. Recent studies have emphasized their importance in cardiac regeneration and repair. As their altered expression affects 3 cardiac function, miRs and lncRNAs could be potential targets for therapeutic intervention. In this context, miR-and lncRNA-based gene therapies are an interesting field for harnessing the complexity of ncRNA-based therapeutic approaches in cardiac diseases. In this review we will focus on lncRNA-and miR-driven regulations of cardiac development and repair. Finally, we will summarize miRs and lncRNAs as promising candidates for the treatment of heart diseases.

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Bmp Signaling Regulates Myocardial Differentiation from Cardiac Progenitors Through a MicroRNA-Mediated Mechanism

Cited by 166 publications

References 51 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

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Interactions between microRNAs and long non-coding RNAs in cardiac development and repair

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