A heart-hand syndrome gene: Tfap2b plays a critical role in the development and remodeling of mouse ductus arteriosus and limb patterning

PLoS One. 2011;6(7):e22908. doi: 10.1371/journal.pone.0022908. Epub 2011 Jul 29.


Background: Patent ductus arteriosus (PDA) is one of the most common forms of congenital heart disease. Mutations in transcription factor TFAP2B cause Char syndrome, a human disorder characterized by PDA, facial dysmorphysm and hand anomalies. Animal research data are needed to understand the mechanisms. The aim of our study was to elucidate the pathogenesis of Char syndrome at the molecular level.

Methodology/principal findings: Gene expression of Tfap2b during mouse development was studied, and newborns of Tfap2b-deficient mice were examined to identify phenotypes. Gel shift assays had been carried out to search for Tfap2 downstream genes. Promoters of candidate genes were cloned into a reporter construct and used to demonstrate their regulation by Tfap2b in cell transfection. In situ hybridizations showed that the murine transcription factor Tfap2b was expressed during the entire development of mouse ductus arteriosus. Histological examination of ductus arteriosus from Tfap2b knockout mice 6 hours after birth revealed that they were not closed. Consequently, the lungs of Tfap2b(-/-) mice demonstrated progressive congestion of the pulmonary capillaries, which was postulated to result secondarily from PDA. In addition, Tfap2b was expressed in the limb buds, particularly in the posterior limb field during development. Lack of Tfap2b resulted in bilateral postaxial accessory digits. Further study indicated that expressions of bone morphogenetic protein (Bmp) genes, which are reported to be involved in the limb patterning and ductal development, were altered in limb buds of Tfap2b-deficient embryos, due to direct control of Bmp2 and Bmp4 promoter activity by Tfap2b.

Conclusions/significance: Tfap2b plays important roles in the development of mouse ductus arteriosus and limb patterning. Loss of Tfap2b results in altered Bmp expression that may cause the heart-limb defects observed in Tfap2b mouse mutants and Char syndrome patients. The Tfap2b knockout mouse may add to the very limited available animal models of PDA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple*
  • Animals
  • Animals, Newborn
  • Bone Morphogenetic Protein 2 / genetics
  • Bone Morphogenetic Protein 4 / genetics
  • Ductus Arteriosus, Patent / etiology*
  • Ductus Arteriosus, Patent / metabolism
  • Ductus Arteriosus, Patent / pathology
  • Electrophoretic Mobility Shift Assay
  • Female
  • Heart Defects, Congenital*
  • Heart Septal Defects, Atrial*
  • Humans
  • In Situ Hybridization
  • Limb Deformities, Congenital / etiology*
  • Limb Deformities, Congenital / metabolism
  • Limb Deformities, Congenital / pathology
  • Lower Extremity Deformities, Congenital*
  • Luciferases / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Phenotype
  • Promoter Regions, Genetic / genetics
  • Transcription Factor AP-2 / physiology*
  • Upper Extremity Deformities, Congenital*


  • Bmp2 protein, mouse
  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 4
  • Transcription Factor AP-2
  • Luciferases

Supplementary concepts

  • Holt-Oram syndrome