The aryl hydrocarbon receptor controls cyclin O to promote epithelial multiciliogenesis
journal contributionposted on 15.10.2020, 08:32 by Matteo Villa, Stefania Crotta, Kevin S Dingwell, Elizabeth MA Hirst, Manolis Gialitakis, Helena Ahlfors, James C Smith, Brigitta Stockinger, Andreas Wack
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.
Air PollutantsAnimalsAnimals, Genetically ModifiedBasic Helix-Loop-Helix Transcription FactorsCell Cycle ProteinsCells, CulturedCyclinsCytochrome P-450 CYP1A1EpidermisGene Expression RegulationInactivation, MetabolicMiceMice, Inbred C57BLMice, KnockoutNuclear ProteinsPromoter Regions, GeneticRNA, MessengerReceptors, Aryl HydrocarbonRespiratory MucosaXenopus ProteinsXenopus laevisWack FC001206Smith FC001157Stockinger FC001159EMBRF-ackLM-ackAS-ack