title: Pax3 and Pax7 play essential safeguard functions against environmental stress-induced birth defects.
abstract: 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.
authors: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center, INSERM U974, CNRS FRE 3617, Institut de Myologie, 75013 Paris, France; INSERM U955 IMRB, Team 10, 94000 Creteil, France; UPEC Paris Est-Creteil University, Faculty of Medicine, 94000 Creteil, France.
authors: Antoine
authors: A
authors: Zalc
authors: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center, INSERM U974, CNRS FRE 3617, Institut de Myologie, 75013 Paris, France; INSERM U955 IMRB, Team 10, 94000 Creteil, France; UPEC Paris Est-Creteil University, Faculty of Medicine, 94000 Creteil, France.
authors: Revital
authors: R
authors: Rattenbach
authors: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center, INSERM U974, CNRS FRE 3617, Institut de Myologie, 75013 Paris, France.
authors: Frédéric
authors: F
authors: Auradé
authors: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center, INSERM U974, CNRS FRE 3617, Institut de Myologie, 75013 Paris, France.
authors: Bruno
authors: B
authors: Cadot
authors: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center, INSERM U974, CNRS FRE 3617, Institut de Myologie, 75013 Paris, France; INSERM U955 IMRB, Team 10, 94000 Creteil, France; UPEC Paris Est-Creteil University, Faculty of Medicine, 94000 Creteil, France; Etablissement Français du Sang, 94017 Creteil, France; Université Paris Est, Ecole Nationale Veterinaire d'Alfort, 94700 Maison-Alfort, France. Electronic address: frederic.relaix@inserm.fr.
authors: Frédéric
authors: F
authors: Relaix
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000013:Congenital Abnormalities / Q000209:etiology / Q000517:prevention & control*; D019465:Craniofacial Abnormalities / Q000139:chemically induced / Q000517:prevention & control*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D020869:Gene Expression Profiling; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor / Q000502:physiology*; D051761:Paired Box Transcription Factors / Q000502:physiology*; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives / Q000633:toxicity; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004785:Environmental Pollutants; D000072041:PAX3 Transcription Factor; D051763:PAX7 Transcription Factor; D051761:Paired Box Transcription Factors; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse; C493957:Cdkn1a protein, mouse; C497322:Pax7 protein, mouse; C068686:Pax3 protein, mouse; C445379:1,2,7,8-tetrachlorodibenzo-p-dioxin