β-Catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1

Sung-Ho Huh, David M. Ornitz

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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-β-catenin signaling negatively regulates Tbx1 expression and that mesenchymal inactivation of β-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-β-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-β-catenin signaling as a crucial upstream regulator of a Tbx1-Fgf8 signaling pathway and suggest that factors that affect Wnt-β-catenin signaling could modify the incidence and severity of DGS.

Original languageEnglish (US)
Pages (from-to)1137-1147
Number of pages11
JournalDevelopment
Volume137
Issue number7
DOIs
StatePublished - Apr 1 2010

Fingerprint

DiGeorge Syndrome
Catenins
Phenotype
Micrognathism
Arteries
Wnt Proteins
Branchial Region
Inborn Genetic Diseases
Parathyroid Glands
Gene Dosage
Incidence
Thoracic Aorta
Thymus Gland
Lung
Genes

Keywords

  • Digeorge syndrome
  • Fgf8
  • Pharyngeal arch
  • Tbx1
  • β-catenin

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Cite this

β-Catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1. / Huh, Sung-Ho; Ornitz, David M.

In: Development, Vol. 137, No. 7, 01.04.2010, p. 1137-1147.

Research output: Contribution to journalArticle

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