Tbx1 controls cardiac neural crest cell migration during arch artery development by regulating<i>Gbx2</i>expression in the pharyngeal ectoderm

Calmont, Amélie; Ivins, Sarah; Bueren, Kelly Lammerts van; Papangeli, Irinna; Kyriakopoulou, Vanessa; Andrews, William D.; Martin, James F.; Moon, Anne M.; Illingworth, Elizabeth; Basson, M. Albert; Scambler, Peter J.

doi:10.1242/dev.028902

Cited by 131 publications

(177 citation statements)

References 80 publications

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“…22 Of note, a pathogenic role for neural crest cells was also suspected for Lujan-Fryns Syndrome with the involvement of MED12, another member of the Mediator complex. 23 In addition, MED13L and other subunits of the Mediator complex were recently shown to have a role in Rb/E2F-induced growth inhibition.…”

Section: Discussionmentioning

confidence: 99%

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Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

Asadollahi

Oneda

Sheth³

et al. 2013

Eur J Hum Genet

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A chromosomal balanced translocation disrupting the MED13L (Mediator complex subunit13-like) gene, encoding a subunit of the Mediator complex, was previously associated with transposition of the great arteries (TGA) and intellectual disability (ID), and led to the identification of missense mutations in three patients with isolated TGA. Recently, a homozygous missense mutation in MED13L was found in two siblings with non-syndromic ID from a consanguineous family. Here, we describe for the first time, three patients with copy number changes affecting MED13L and delineate a recognizable MED13L haploinsufficiency syndrome. Using high resolution molecular karyotyping, we identified two intragenic de novo frameshift deletions, likely resulting in haploinsufficiency, in two patients with a similar phenotype of hypotonia, moderate ID, conotruncal heart defect and facial anomalies. In both, Sanger sequencing of MED13L did not reveal any pathogenic mutation and exome sequencing in one patient showed no evidence for a non-allelic second hit. A further patient with hypotonia, learning difficulties and perimembranous VSD showed a 1 Mb de novo triplication in 12q24.2, including MED13L and MAP1LC3B2. Our findings show that MED13L haploinsufficiency in contrast to the previously observed missense mutations cause a distinct syndromic phenotype. Additionally, a MED13L copy number gain results in a milder phenotype. The clinical features suggesting a neurocristopathy may be explained by animal model studies indicating involvement of the Mediator complex subunit 13 in neural crest induction.

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Section: Discussionmentioning

confidence: 99%

“…The third patient is a girl born 5 days preterm with a history of transient but marked fetal hydrops during pregnancy (weeks [16][17][18][19][20][21][22][23][24][25]. Her birth weight was 2200 g (o3rd centile) and the length was 47 cm (3rd centile).…”

Section: Patientmentioning

confidence: 99%

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

Asadollahi

Oneda

Sheth³

et al. 2013

Eur J Hum Genet

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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%

“…Surprisingly, we found that Tbx1 and p53 cooccupy chromatin segments, suggesting that they have shared targets. Indeed, we found that Gbx2, a gene required during cardiovascular development and known to genetically interact with Tbx1 (16,17), is targeted by both transcription factors. Specifically, it is down-regulated by Tbx1 deletion, but its expression is reestablished to wild-type levels in the presence of Trp53 deletion.…”

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confidence: 94%

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, a putative T-box transcription factor, is expressed in the pharyngeal endoderm, ectoderm, and core mesoderm [4][5][6]. Celltype-specific inactivation in mice and analysis of Tbx1 downstream targets indicate that it plays multiple roles in endoderm, mesoderm, and ectoderm cells during pharyngeal development [7][8][9]. In humans, Tbx1 is involved in the DiGeorge syndrome, which is associated with cardiac malformations as well as other developmental anomalies of organs and structures derived from the pharyngeal apparatus [10].…”

Section: Introductionmentioning

confidence: 99%

Tbx1 Modulates Endodermal and Mesodermal Differentiation from Mouse Induced Pluripotent Stem Cells

Yan

Su²,

Song³

et al. 2014

Stem Cells and Development

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The T-box transcriptional factor (Tbx) family of transcriptional factors has distinct roles in a wide range of embryonic differentiation or response pathways. Tbx1, a T-box transcription factor, is an important gene for the human congenital disorder 22q11.2 deletion syndrome. Induced pluripotent stem cell (iPSC) technology offers new opportunities for both elucidation of the pathogenesis of diseases and the development of stem-cell-based therapies. In this study, we generated iPSCs from Tbx1 -/ -and Tbx1 + / + fibroblasts and investigated the spontaneous differentiation potential of iPSCs by detailed lineage analysis of the iPSC-derived embryoid bodies. Undifferentiated Tbx1 -/ -and Tbx1 + / + iPSCs showed similar expression levels of pluripotent markers. The ability of the Tbx1 -/ -iPSCs to generate endodermal and mesodermal lineages was compromised upon spontaneous differentiation into embryonic bodies. Restoration of Tbx1 expression in the Tbx1 -/ -iPSCs to normal levels using an inducible lentiviral system rescued these cells from the potential of defective differentiation. Interestingly, overexpression of Tbx1 in the Tbx1 -/ -iPSCs to higher levels than in the Tbx1 + / + iPSCs again led to a defective differentiation potential. Additionally, we observed that expression of fibroblast growth factor (FGF) 10 and FGF8 was downregulated in the Tbx1 -/ -iPSC-derived cells, which suggests that Tbx1 regulates the expression of FGFs. Taken together, our results implicated the Tbx1 level as an important determinant of endodermal and mesodermal lineage differentiation during embryonic development.

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Tbx1 controls cardiac neural crest cell migration during arch artery development by regulatingGbx2expression in the pharyngeal ectoderm

Cited by 131 publications

References 80 publications

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

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

Tbx1 Modulates Endodermal and Mesodermal Differentiation from Mouse Induced Pluripotent Stem Cells

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