Pax3 and Pax7 play essential safeguard functions against environmental stress-induced birth defects

Dev Cell. 2015 Apr 6;33(1):56-66. doi: 10.1016/j.devcel.2015.02.006. Epub 2015 Mar 19.


Exposure to environmental teratogenic pollutant leads to severe birth defects. However, the biological events underlying these developmental abnormalities remain undefined. Here, we report a molecular link between an environmental stress response pathway and key developmental genes during craniofacial development. Strikingly, mutant mice with impaired Pax3/7 function display severe craniofacial defects. We show that these are associated with an upregulation of the signaling pathway mediated by the Aryl hydrocarbon receptor (AHR), the receptor to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), revealing a genetic interaction between Pax3 and AHR signaling. Activation of AHR signaling in Pax3-deficient embryos drives facial mesenchymal cells out of the cell cycle through the upregulation of p21 expression. Accordingly, inhibiting AHR activity rescues the cycling status of these cells and the facial closure of Pax3/7 mutants. Together, our findings demonstrate that the regulation of AHR signaling by Pax3/7 is required to protect against TCDD/AHR-mediated teratogenesis during craniofacial development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Cell Lineage / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Congenital Abnormalities / etiology
  • Congenital Abnormalities / prevention & control*
  • Craniofacial Abnormalities / chemically induced
  • Craniofacial Abnormalities / prevention & control*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / drug effects
  • Embryo, Mammalian / metabolism
  • Environmental Pollutants / toxicity*
  • Female
  • Gene Expression Profiling
  • Mice
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis
  • PAX3 Transcription Factor
  • PAX7 Transcription Factor / physiology*
  • Paired Box Transcription Factors / physiology*
  • Polychlorinated Dibenzodioxins / analogs & derivatives
  • Polychlorinated Dibenzodioxins / toxicity
  • Pregnancy
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction


  • Ahr protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Environmental Pollutants
  • PAX3 Transcription Factor
  • PAX7 Transcription Factor
  • Paired Box Transcription Factors
  • Pax7 protein, mouse
  • Polychlorinated Dibenzodioxins
  • RNA, Messenger
  • Receptors, Aryl Hydrocarbon
  • Pax3 protein, mouse
  • 1,2,7,8-tetrachlorodibenzo-p-dioxin