| Tbx1 Genetically Interacts With the TGFβ/BMP Inhibitor Smad7 During Great Vessel Remodeling. | |
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MedLine Citation:
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PMID: 23011393 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Rationale: Growth and remodeling of the pharyngeal arch arteries is vital for the development of a mature great vessel system. Dysmorphogenesis of the fourth arch arteries can result in interruption of the aortic arch type-B, typically found in DiGeorge syndrome (DGS). Tbx1 haploinsufficient embryos, which model DGS, display fourth arch artery defects during formation of the vessels. Recovery from such defects is a documented yet unexplained phenotype in Tbx1 haploinsufficiency. Objective: To understand the nature of fourth arch artery growth recovery in Tbx1 haploinsufficiency, and its underlying genetic control. Methods and Results: We categorized vessel phenotypes of Tbx1 heterozygotes as hypoplastic or aplastic at the conclusion of pharyngeal artery formation and compared these against the frequency of vessel defects scored at the end of great vessel development. The frequency of hypoplastic vessels decreased during embryogenesis, whereas no reduction of vessel aplasia was seen, implying recovery is due to remodeling of hypoplastic vessels. We showed that Smad7, an inhibitory Smad within the TGFβ pathway, is regulated by Tbx1, is required for arch artery remodeling, and genetically interacts with Tbx1 in this process. Tbx1 and Tbx1;Smad7 haploinsufficiency affected several remodeling processes, however, concurrent haploinsufficiency particularly impacted on the earliest stage of vascular smooth muscle cell vessel coverage and subsequent fibronectin deposition. Conditional reconstitution of Smad7 with a Tbx1Cre driver indicated that the interaction between the two genes is cell autonomous. Conclusions: Tbx1 acts upstream of Smad7 controlling vascular smooth muscle and extracellular matrix (ECM) investment of the fourth arch artery. |
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Authors:
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Irinna Papangeli; Peter Scambler |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-9-25 |
Journal Detail:
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Title: Circulation research Volume: - ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2012 Sep |
Date Detail:
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Created Date: 2012-9-26 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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UCL Institute of Child Health. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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