Beta-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1.
DiGeorge syndrome (DGS) is a common genetic disease characterized by pharyngeal apparatus malformations and defects in cardiovascular, craniofacial and glandular development. TBX1 is the most likely candidate disease-causing gene and is located within a 22q11.2 chromosomal deletion that is associated with most cases of DGS. Here, we show that canonical Wnt-beta-catenin signaling negatively regulates Tbx1 expression and that mesenchymal inactivation of beta-catenin (Ctnnb1) in mice caused abnormalities within the DGS phenotypic spectrum, including great vessel malformations, hypoplastic pulmonary and aortic arch arteries, cardiac malformations, micrognathia, thymus hypoplasia and mislocalization of the parathyroid gland. In a heterozygous Fgf8 or Tbx1 genetic background, ectopic activation of Wnt-beta-catenin signaling caused an increased incidence and severity of DGS-like phenotypes. Additionally, reducing the gene dosage of Fgf8 rescued pharyngeal arch artery defects caused by loss of Ctnnb1. These findings identify Wnt-beta-catenin signaling as a crucial upstream regulator of a Tbx1-Fgf8 signaling pathway and suggest that factors that affect Wnt-beta-catenin signaling could modify the incidence and severity of DGS.
Huh
Sung-Ho
SH
Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA.
Ornitz
David M
DM
D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001934:Branchial Region / Q000002:abnormalities / Q000033:anatomy & histology / Q000196:embryology; D004062:DiGeorge Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017403:In Situ Hybridization; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011247:Pregnancy; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
C496457:Fgf8 protein, mouse; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; C108625:TBX1 protein, human; C491573:Tbx1 protein, mouse; D051879:Twist-Related Protein 1; C096852:Twist2 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; D051524:Fibroblast Growth Factor 8