Anomalous looping, atrioventricular cushion dysplasia, and unilateral ventricular hypoplasia in the mouse embryos with right isomerism induced by retinoic acid

Yasui, Hiroshi; Morishima, Masae; Nakazawa, Makoto; Aikawa, Eizo

doi:10.1002/(sici)1097-0185(199802)250:2<210::aid-ar11>3.0.co;2-r

Cited by 32 publications

(25 citation statements)

References 29 publications

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“…As the Tbx2 expression in the AVC region occurs earlier than that in the OFT region (Habets et al, 2002), the administration of RA at E8.5 might be too late to suppress Tbx2 expression in the AVC region. In fact, previous data indicated that abnormal AVC endocardial EMT was also induced by excess RA when embryos were treated with RA at E6.5 (Yasui et al, 1998). A second possibility is that different sensitivities to RA exist among different heart-forming lineages.…”

Section: Discussionmentioning

confidence: 96%

Ectopic retinoic acid signaling affects outflow tract cushion development through suppression of the myocardial Tbx2-Tgfβ2 pathway

et al. 2012

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SUMMARYThe progress of molecular genetics has enabled us to identify the genes responsible for congenital heart malformations. However, recent studies suggest that congenital heart diseases are induced not only by mutations in certain genes, but also by abnormal maternal factors. A high concentration of maternal retinoic acid (RA), the active derivative of vitamin A, is well known as a teratogenic agent that can cause developmental defects. Our previous studies have shown that the maternal administration of RA to mice within a narrow developmental window induces outflow tract (OFT) septum defects, a condition that closely resembles human transposition of the great arteries (TGA), although the responsible factors and pathogenic mechanisms of the TGA induced by RA remain unknown. We herein demonstrate that the expression of Tbx2 in the OFT myocardium is responsive to RA, and its downregulation is associated with abnormal OFT development. We found that RA could directly downregulate the Tbx2 expression through a functional retinoic acid response element (RARE) in the Tbx2 promoter region, which is also required for the initiation of Tbx2 transcription during OFT development. Tgfb2 expression was also downregulated in the RA-treated OFT region and was upregulated by Tbx2 in a culture system. Moreover, defective epithelial-mesenchymal transition caused by the excess RA was rescued by the addition of Tgf2 in an organ culture system. These data suggest that RA signaling participates in the Tbx2 transcriptional mechanism during OFT development and that the Tbx2-Tgf2 cascade is one of the key pathways involved in inducing the TGA phenotype.

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Section: Discussionmentioning

confidence: 96%

Ectopic retinoic acid signaling affects outflow tract cushion development through suppression of the myocardial Tbx2-Tgfβ2 pathway

et al. 2012

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“…35,36 In this animal model, TGA could be found in the presence of both D-and L-loops of the ventricles (ie, complete TGA and congenitally corrected TGA), 35 and treatment with retinoic acid in mouse embryos also could induce looping anomalies with right isomerism. 37 Moreover, complete TGA (ie, with situs solitus and D-loop ventricle) can be present among heart defects of homozygous iv/iv mice presenting with a high prevalence of visceral heterotaxy and lateralization anomalies. 38 Animal models, therefore, support a common pathogenetic mechanism involved in causing some cases of complete TGA along with congenitally corrected TGA and other laterality defects.…”

Section: Discussionmentioning

confidence: 99%

Complete Transposition of the Great Arteries

et al. 2001

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Background Transposition of the great arteries (TGA) is considered to be associated only rarely with genetic syndromes and to have a low risk of precurrence among relatives of affected patients. Because most family studies have involved a relatively small number of patients and evaluated all types of TGA as a single group, we performed a large, prospective study investigating the precurrence of congenital heart disease in families of children with complete, nonsyndromic TGA. Methods and Results From January 1997 through December 2000, 370 patients with nonsyndromic, complete TGA were consecutively evaluated and enrolled in the study. The occurrence of cardiac and noncardiac anomalies among relatives of the probands was investigated. Relatives with congenital heart disease were found in 37 of 370 families (10%), including 5 of 37 families (13.5%) with more than one affected relative. TGA itself was the most common precurrent malformation: complete TGA occurred in 6 families and congenitally corrected TGA occurred in 5 families. Precurrence risks for congenital heart disease were calculated at 1.8% (8 of 436) for siblings, 0.5% (4 of 740) for parents, 0.5% (16 of 3261) for first cousins, 0.2% (4 of 2101) for uncles/aunts, and 0.06% (1 of 1480) for grandparents. Conclusions The present study shows that TGA is not always sporadic in families. Precurrence of concordant cardiac defects within affected family members supports monogenic or oligogenic inheritance of TGA in certain kindreds. Moreover, the occurrence of complete TGA and congenitally corrected TGA among first-degree relatives in several different families strongly suggests an underlying pathogenetic link between these 2 malformations that has been previously unrecognized.

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“…34 Amino acid exchanges caused by missense mutations could alter the ability of PROSIT240 to interact with target activators or repressors. Understanding more about the mechanisms leading to dTGA might also help to determine whether dTGA could be considered a manifestation of a left-right laterality defect concerning the heart, a point that has been raised based on data from animal models 35,36 and the fact that ZIC3 and CFC1 mutations are detected both in patients with dTGA and in heterotaxy problems. 8,11 In animal models, most interestingly, Pitx2 Ϫ/Ϫ and Dvl Ϫ/Ϫ mice present with outflow tract abnormalities, including TGA and laterality defects.…”

Section: Muncke Et Al Prosit240 Mutations In Patients With Dtgamentioning

confidence: 99%

Missense Mutations and Gene Interruption in PROSIT240 , a Novel TRAP240 -Like Gene, in Patients With Congenital Heart Defect (Transposition of the Great Arteries)

et al. 2003

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Background-Congenital heart disease represents the most common severe birth defect, affecting 0.7% to 1% of all neonates, among whom 5% to 7% display transposition of the great arteries (TGA). TGA represents a septation defect of the common outflow tract of the heart, manifesting around the fifth week during embryonic development. Despite its high prevalence, very little is known about the pathogenesis of this disease. Methods and Results-Using a positional cloning approach, we isolated a novel gene, PROSIT240 (also termed THRAP2), that is interrupted in a patient with a chromosomal translocation and who displays TGA and mental retardation. High expression of PROSIT240 within the heart (aorta) and brain (cerebellum) was well correlated with the malformations observed in the patient and prompted further analyses. PROSIT240 shows significant homology to the nuclear receptor coactivator TRAP240, suggesting it to be a new component of the thyroid hormone receptor-associated protein (TRAP) complex. Interestingly, several TRAP components have been previously shown to be important in early embryonic development in various organisms, making PROSIT240 an excellent candidate gene to be correlated to the patient's phenotype. Subsequent mutational screening of 97 patients with isolated dextro-looped TGA revealed 3 missense mutations in PROSIT240, which were not detected in 400 control chromosomes. Conclusions-Together, these genetic data suggest that PROSIT240 is involved in early heart and brain development.

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Anomalous looping, atrioventricular cushion dysplasia, and unilateral ventricular hypoplasia in the mouse embryos with right isomerism induced by retinoic acid

Cited by 32 publications

References 29 publications

Ectopic retinoic acid signaling affects outflow tract cushion development through suppression of the myocardial Tbx2-Tgfβ2 pathway

Ectopic retinoic acid signaling affects outflow tract cushion development through suppression of the myocardial Tbx2-Tgfβ2 pathway

Complete Transposition of the Great Arteries

Missense Mutations and Gene Interruption in PROSIT240 , a Novel TRAP240 -Like Gene, in Patients With Congenital Heart Defect (Transposition of the Great Arteries)

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