title: Tbx1 genetically interacts with the transforming growth factor-β/bone morphogenetic protein inhibitor Smad7 during great vessel remodeling.
abstract: BACKGROUND
  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.
  
  
  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.affiliation: UCL-ICH, 30 Guilford St, London WC1N 1EH, UK.
authors.forename: Irinna
authors.initials: I
authors.lastname: Papangeli
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
mesh_terms: D000818:Animals; D001158:Arteries / Q000002:abnormalities / Q000378:metabolism*; D001665:Binding Sites; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001934:Branchial Region / Q000002:abnormalities / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D004062:DiGeorge Syndrome / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D057895:Haploinsufficiency; D006579:Heterozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009024:Morphogenesis; D009131:Muscle, Smooth, Vascular / Q000002:abnormalities / Q000378:metabolism; D010641:Phenotype; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D051906:Smad7 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D005353:Fibronectins; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D016212:Transforming Growth Factor beta