<i>Tbx1</i>
            Genetically Interacts With the Transforming Growth Factor-β/Bone Morphogenetic Protein Inhibitor
            <i>Smad7</i>
            During Great Vessel Remodeling

Papangeli, Irinna; Scambler, Peter J.

doi:10.1161/circresaha.112.270223

Cited by 47 publications

(47 citation statements)

References 48 publications

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“…4–5) and the online Figure IIB in (Papangeli and Scambler, 2013). Consistent with these data, we found that integrin α5 was efficiently depleted from arch artery endothelium in integrin α5 flox/− ; Mesp1 Cre+ mutants (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mesodermal expression of integrin α5β1 regulates neural crest development and cardiovascular morphogenesis

Dong¹,

Wang²,

Mittal³

et al. 2014

Developmental Biology

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Integrin α5-null embryos die in mid-gestation from severe defects in cardiovascular morphogenesis, which stem from defective development of the neural crest, heart and vasculature. To investigate the role of integrin α5β1 in cardiovascular development, we used the Mesp1Cre knock-in strain of mice to ablate integrin α5 in the anterior mesoderm, which gives rise to all of the cardiac and many of the vascular and muscle lineages in the anterior portion of the embryo. Surprisingly, we found that mutant embryos displayed numerous defects related to the abnormal development of the neural crest such as cleft palate, ventricular septal defect, abnormal development of hypoglossal nerves, and defective remodeling of the aortic arch arteries. We found that defects in arch artery remodeling stem from the role of mesodermal integrin α5β1 in neural crest proliferation and differentiation into vascular smooth muscle cells, while proliferation of pharyngeal mesoderm and differentiation of mesodermal derivatives into vascular smooth muscle cells was not defective. Taken together our studies demonstrate a requisite role for mesodermal integrin α5β1 in signaling between the mesoderm and the neural crest, thereby regulating neural crest-dependent morphogenesis of essential embryonic structures.

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Section: Resultsmentioning

confidence: 99%

Mesodermal expression of integrin α5β1 regulates neural crest development and cardiovascular morphogenesis

Dong¹,

Wang²,

Mittal³

et al. 2014

Developmental Biology

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“…Four RLIM-affected males presented with CHD resembling CHD types described in the 22q11-deletion syndrome. TBX1, which resides in this 22q11 chromosomal region, is very dose sensitive and is involved in the formation of the secondary heart field together with its targets, e.g., SMAD7 [79], SHH, FGF8 and BMP4 [80], indicating once again the involvement of subtle (dose) dysregulation of RLIM downstream effectors can have consequences for the expression of the clinical phenotype.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

et al. 2018

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RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes cosegregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

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“…To identify putative shared targets, we followed a candidate gene approach. We considered three Tbx1 target genes that are known to interact with Tbx1 during fourth PAA development: Gbx2, Smad7, and Wnt5a (17,24,25). We first tested the expression of these genes in WT, Tbx1 +/− , Trp53 +/− , and Tbx1 +/− ; Trp53 +/− E8.5 embryos using quantitative reverse transcription PCR.…”

Section: Trp53 Mutation Modifies the Hypomorphic But Not The Null Tbx1mentioning

confidence: 99%

p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome

Caprio

Baldini

2014

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

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Significance The 22q11.2 deletion is the most common known genetic cause of congenital heart disease (CHD). The haploinsufficiency of TBX1 has been identified as the cause of CHD. Using mouse models of the disease, we found that reduced dosage of p53 suppresses the Tbx1 mutant phenotype. Tbx1 and p53 proteins coregulate the gene Gbx2 , which is required for cardiovascular development. Gbx2 expression is positively regulated by Tbx1, whereas suppression of p53 results in reduced levels of the repressive chromatin mark H3K27me3 at a genetic element occupied by both Tbx1 and p53. These data illustrate a mechanism by which reduced p53, by genetic or pharmacological means, can counterbalance the consequences of reduced dosage of Tbx1.

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Tbx1 Genetically Interacts With the Transforming Growth Factor-β/Bone Morphogenetic Protein Inhibitor Smad7 During Great Vessel Remodeling

Cited by 47 publications

References 48 publications

Mesodermal expression of integrin α5β1 regulates neural crest development and cardiovascular morphogenesis

Mesodermal expression of integrin α5β1 regulates neural crest development and cardiovascular morphogenesis

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome

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