Document Detail


Tbx1 genetically interacts with the transforming growth factor-β/bone morphogenetic protein inhibitor Smad7 during great vessel remodeling.
MedLine Citation:
PMID:  23011393     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: Growth and remodeling of the pharyngeal arch arteries are 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. Tbx1 haploinsufficient embryos, which model DiGeorge syndrome, 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 attributable to remodeling of hypoplastic vessels. We showed that Smad7, an inhibitory Smad within the transforming growth factor-β 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 2 genes is cell autonomous.
CONCLUSIONS: Tbx1 acts upstream of Smad7 controlling vascular smooth muscle and extracellular matrix investment of the fourth arch artery.
Authors:
Irinna Papangeli; Peter J Scambler
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-09-25
Journal Detail:
Title:  Circulation research     Volume:  112     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-04     Completed Date:  2013-02-27     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  90-102     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Arteries / abnormalities,  metabolism*
Binding Sites
Bone Morphogenetic Proteins / metabolism*
Branchial Region / abnormalities,  metabolism*
Cell Differentiation
Cell Lineage
Cell Movement
Cell Proliferation
DiGeorge Syndrome / embryology,  genetics,  metabolism*
Fibronectins / metabolism
Gene Expression Regulation, Developmental
Gestational Age
Haploinsufficiency
Heterozygote
Mice
Mice, Inbred C57BL
Mice, Transgenic
Morphogenesis
Muscle, Smooth, Vascular / abnormalities,  metabolism
Phenotype
Regulatory Sequences, Nucleic Acid
Signal Transduction*
Smad7 Protein / deficiency,  genetics,  metabolism*
T-Box Domain Proteins / deficiency,  genetics,  metabolism*
Transforming Growth Factor beta / metabolism*
Grant Support
ID/Acronym/Agency:
RG/10/13/28570//British Heart Foundation; RG/15/13/28570//British Heart Foundation
Chemical
Reg. No./Substance:
0/Bone Morphogenetic Proteins; 0/Fibronectins; 0/Smad7 Protein; 0/Smad7 protein, mouse; 0/T-Box Domain Proteins; 0/Tbx1 protein, mouse; 0/Transforming Growth Factor beta

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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