Defective ALK5 signaling in the neural crest leads to increased postmigratory neural crest cell apoptosis and severe outflow tract defects

Wang, Jikui; Nagy, Andre; Larsson, Jonas; Dudáš, Marek; Sucov, Henry M.; Kaartinen, Vesa

doi:10.1186/1471-213x-6-51

Cited by 82 publications

(29 citation statements)

References 44 publications

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“…Because our strategy to inhibit Wnt signaling competence was limited to the SHF, the defect in CNC patterning indicates that there is a nonautonomous signal acting downstream of ␤-catenin. Published data reveal that inactivation of Bmp ligands in SHF, and type I Bmp receptors in CNC resulted in defective cardiac cushion development, supporting the notion that Bmp signals from SHF regulate development of the CNC (17,(42)(43)(44).…”

Section: Wnt Signaling Is Critical For Development Of the Right Ventrmentioning

confidence: 74%

Canonical Wnt signaling functions in second heart field to promote right ventricular growth

Wang

et al. 2007

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

176

138

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The second heart field (SHF), progenitor cells that are initially sequestered outside the heart, migrates into the heart and gives rise to endocardium, myocardium, and smooth muscle. Because of its distinct developmental history, the SHF is likely subjected to different signals from that of the first heart field. Previous experiments revealed that canonical Wnt signaling negatively regulated first heart field specification. We inactivated the obligate canonical Wnt effector ␤-catenin using a ␤-catenin conditional null allele and the Mef2c AHF cre driver that directs cre activity specifically in SHF. We also expressed a stabilized form of ␤-catenin to model continuous Wnt signaling in SHF. Our data indicate that Wnt signaling acts in a positive fashion to promote right ventricular and interventricular myocardial expansion. Cyclin D2 and Tgf␤2 expression was drastically reduced in ␤-catenin loss-of-function mutants, indicating that Wnt signaling is required for patterning and expansion of SHF derivatives. Our findings reveal that Wnt signaling plays a major positive role in promoting growth and diversification of SHF precursors into right ventricular and interventricular myocardium.conditional genetics ͉ cardiac progenitor ͉ mouse ͉ development

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Section: Wnt Signaling Is Critical For Development Of the Right Ventrmentioning

confidence: 74%

Canonical Wnt signaling functions in second heart field to promote right ventricular growth

Wang

et al. 2007

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

176

138

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“…40 Increased post-migratory neural crest cell apoptosis in mice defective for Alk5 leads to severe outflow tract defects. 41 Deregulation of TCL1B expression by epimutation could therefore contribute to CHD by secondary disruption of AKT signaling. The unavailability of additional tissue from these cases with TCL1B epimutations precluded further functional analyses.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation abnormalities in congenital heart disease

et al. 2015

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Congenital heart defects represent the most common malformation at birth, occurring also in »50% of individuals with Down syndrome. Congenital heart defects are thought to have multifactorial etiology, but the main causes are largely unknown. We have explored the global methylation profile of fetal heart DNA in comparison to blood DNA from control subjects: an absolute correlation with the type of tissue was detected. Pathway analysis revealed a significant enrichment of differential methylation at genes related to muscle contraction and cardiomyopathies in the developing heart DNA. We have also searched for abnormal methylation profiles on developing heart-tissue DNA of syndromic and non-syndromic congenital heart defects. On average, 3 regions with aberrant methylation were detected per sample and 18 regions were found differentially methylated between groups. Several epimutations were detected in candidate genes involved in growth regulation, apoptosis and folate pathway. A likely pathogenic hypermethylation of several intragenic sites at the MSX1 gene, involved in outflow tract morphogenesis, was found in a fetus with isolated heart malformation. In addition, hypermethylation of the GATA4 gene was present in fetuses with Down syndrome with or without congenital heart defects, as well as in fetuses with isolated heart malformations. Expression deregulation of the abnormally methylated genes was detected. Our data indicate that epigenetic alterations of relevant genes are present in developing heart DNA in fetuses with both isolated and syndromic heart malformations. These epimutations likely contribute to the pathogenesis of the malformation by cis-acting effects on gene expression.

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“…99,100 Null mutants for the TGFβ receptor genes, Tgfbr1 and Tgfbr2, are embryonic lethal in mice, but tissue specific deletion of TGFβ receptor genes support a role for TGFβ signaling in development of the OFT. 101,102 Targeted deletion of Tgfbr1 or Tgfbr2 in neural crest cells leads to OFT defects (PTA, interrupted aortic arch and ventricular septal defect [VSD]), strongly suggesting that TGFβ signaling is necessary for cardiac neural crest cells to promote normal septation of the OFT. [101][102][103] Other mouse models with targeted deletions in BMP/TGFβ signaling Overview on developmental stages of the heart.…”

Section: Heart Development Is Coordinated By Multiple Signaling Networkmentioning

confidence: 99%

“…101,102 Targeted deletion of Tgfbr1 or Tgfbr2 in neural crest cells leads to OFT defects (PTA, interrupted aortic arch and ventricular septal defect [VSD]), strongly suggesting that TGFβ signaling is necessary for cardiac neural crest cells to promote normal septation of the OFT. [101][102][103] Other mouse models with targeted deletions in BMP/TGFβ signaling Overview on developmental stages of the heart. The cardiac crescent is formed around day 15 in humans.…”

Section: Heart Development Is Coordinated By Multiple Signaling Networkmentioning

confidence: 99%

Cilia and coordination of signaling networks during heart development

et al. 2013

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Defective ALK5 signaling in the neural crest leads to increased postmigratory neural crest cell apoptosis and severe outflow tract defects

Cited by 82 publications

References 44 publications

Canonical Wnt signaling functions in second heart field to promote right ventricular growth

Canonical Wnt signaling functions in second heart field to promote right ventricular growth

DNA methylation abnormalities in congenital heart disease

Cilia and coordination of signaling networks during heart development

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