title: The aryl hydrocarbon receptor controls cyclin O to promote epithelial multiciliogenesis.
abstract: Epithelia function as barriers against environmental insults and express the transcription factor aryl hydrocarbon receptor (AhR). However, AhR function in these tissues is unknown. Here we show that AhR regulates multiciliogenesis in both murine airway epithelia and in Xenopus laevis epidermis. In air-exposed airway epithelia, induction of factors required for multiciliogenesis, including cyclin O (Ccno) and Multicilin (Mcidas), is AhR dependent, and air exposure induces AhR binding to the Ccno promoter. Submersion and hypoxic conditions impede AhR-dependent Ccno induction. This is mediated by the persistence of Notch signalling, as Notch blockade renders multiciliogenesis and Ccno induction by AhR independent from air exposure. In contrast to Ccno induction, air exposure does not induce the canonical AhR target cytochrome P450 1a1 (Cyp1a1). Inversely, exposure to AhR ligands induces Cyp1a1 but not Ccno and impeded ciliogenesis. These data indicate that AhR involvement in detoxification of environmental pollutants may impede its physiological role, resulting in respiratory pathology.
authors.affiliation: Laboratory of AhRimmunity, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: Matteo
authors.initials: M
authors.lastname: Villa
authors.affiliation: Laboratory of Immunoregulation, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: Stefania
authors.identifier: 0000-0003-4676-8616
authors.initials: S
authors.lastname: Crotta
authors.affiliation: Laboratory of Developmental Biology, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Dingwell
authors.affiliation: EM Technology Platform, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: Elizabeth M A
authors.initials: EM
authors.lastname: Hirst
authors.affiliation: Laboratory of AhRimmunity, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: Manolis
authors.initials: M
authors.lastname: Gialitakis
authors.affiliation: Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Helena
authors.initials: H
authors.lastname: Ahlfors
authors.affiliation: Laboratory of Developmental Biology, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: James C
authors.identifier: 0000-0003-2413-9392
authors.initials: JC
authors.lastname: Smith
authors.affiliation: Laboratory of AhRimmunity, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: Brigitta
authors.initials: B
authors.lastname: Stockinger
authors.affiliation: Laboratory of Immunoregulation, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
authors.forename: Andreas
authors.identifier: 0000-0001-5226-2991
authors.initials: A
authors.lastname: Wack
mesh_terms: D000393:Air Pollutants / Q000493:pharmacokinetics; D000818:Animals; D030801:Animals, Genetically Modified; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004817:Epidermis / Q000378:metabolism; D005786:Gene Expression Regulation; D008658:Inactivation, Metabolic; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D029867:Xenopus Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D000393:Air Pollutants; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D016213:Cyclins; D019363:Cytochrome P-450 CYP1A1; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D029867:Xenopus Proteins; C484722:Ahr protein, mouse; C000605590:Mcidas protein, mouse; C476769:aryl hydrocarbon receptor, Xenopus; C539096:cyclin O, mouse; C571015:multicilin, Xenopus