Linked Life Data

16556915

Source:http://linkedlifedata.com/resource/pubmed/id/16556915

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pubmed-article:16556915pubmed:abstractTextIndividuals with 22q11 deletion syndrome (22q11DS; DiGeorge/velo-cardio-facial syndrome) have multiple congenital malformations, including cardiovascular defects. Most individuals with this syndrome possess 1.5-3.0 Mb hemizygous 22q11.2 deletions. The T-box transcription factor TBX1, lies within the nested 1.5 Mb interval and is a strong candidate for its etiology. Inactivation of Tbx1 in the mouse results in neonatal lethality owing to the presence of a single cardiac outflow tract. One important goal is to understand the molecular pathogenesis of cardiovascular defects in this syndrome. However, the molecular pathways of Tbx1 are still largely unexplored. Here, we show that Tbx1 is co-expressed with the bicoid-like homeodomain transcription factor Pitx2 in secondary heart field cells in the pharyngeal mesenchyme. In situ hybridization studies in Tbx1(-/-) mouse embryos revealed downregulation of Pitx2 in these cells. To test for a possible genetic interaction, we intercrossed Tbx1(+/-) and Pitx2(+/-) mice. Tbx1(+/-); Pitx2(+/-) mice died perinatally with cardiac defects, including double outlet right ventricle, and atrial and ventricular septal defects, all occurring with variable penetrance. An enhancer located between exons 4 and 5 in which a putative T-half site was identified near an Nkx2.5-binding site regulates asymmetric expression of Pitx2. We show using in vitro studies that Tbx1 binds to this site and activates the Pitx2 enhancer with the synergistic action of Nkx2.5. The results presented in this study unravel a novel Tbx1-Pitx2 pathway linking Tbx1 to asymmetric cardiac morphogenesis.lld:pubmed
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pubmed-article:16556915pubmed:dateRevised2008-11-21lld:pubmed
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pubmed-article:16556915pubmed:articleTitleTbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field.lld:pubmed
pubmed-article:16556915pubmed:affiliationDepartment of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.lld:pubmed
pubmed-article:16556915pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:16556915pubmed:publicationTypeResearch Support, Non-U.S. Gov'tlld:pubmed
pubmed-article:16556915pubmed:publicationTypeResearch Support, N.I.H., Extramurallld:pubmed
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