title: TAp73 is a central transcriptional regulator of airway multiciliogenesis.
abstract: Motile multiciliated cells (MCCs) have critical roles in respiratory health and disease and are essential for cleaning inhaled pollutants and pathogens from airways. Despite their significance for human disease, the transcriptional control that governs multiciliogenesis remains poorly understood. Here we identify TP73, a p53 homolog, as governing the program for airway multiciliogenesis. Mice with TP73 deficiency suffer from chronic respiratory tract infections due to profound defects in ciliogenesis and complete loss of mucociliary clearance. Organotypic airway cultures pinpoint TAp73 as necessary and sufficient for basal body docking, axonemal extension, and motility during the differentiation of MCC progenitors. Mechanistically, cross-species genomic analyses and complete ciliary rescue of knockout MCCs identify TAp73 as the conserved central transcriptional integrator of multiciliogenesis. TAp73 directly activates the key regulators FoxJ1, Rfx2, Rfx3, and miR34bc plus nearly 50 structural and functional ciliary genes, some of which are associated with human ciliopathies. Our results position TAp73 as a novel central regulator of MCC differentiation.
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA;
authors.forename: Alice
authors.initials: A
authors.lastname: Nemajerova
authors.affiliation: Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany;
authors.forename: Daniela
authors.initials: D
authors.lastname: Kramer
authors.affiliation: Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794, USA;
authors.forename: Saul S
authors.initials: SS
authors.lastname: Siller
authors.affiliation: Department of Internal Medicine V, Saarland University, Homburg 66421, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Herr
authors.affiliation: Computational Systems Biology, German Center for Neurodegenerative Diseases, 37077 Göttingen, Germany;
authors.forename: Orr
authors.initials: O
authors.lastname: Shomroni
authors.affiliation: Computational Systems Biology, German Center for Neurodegenerative Diseases, 37077 Göttingen, Germany;
authors.forename: Tonatiuh
authors.initials: T
authors.lastname: Pena
authors.affiliation: Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany;
authors.forename: Cristina
authors.initials: C
authors.lastname: Gallinas Suazo
authors.affiliation: Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany;
authors.forename: Katharina
authors.initials: K
authors.lastname: Glaser
authors.affiliation: Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany;
authors.forename: Merit
authors.initials: M
authors.lastname: Wildung
authors.affiliation: Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany;
authors.forename: Henrik
authors.initials: H
authors.lastname: Steffen
authors.affiliation: Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany;
authors.forename: Anusha
authors.initials: A
authors.lastname: Sriraman
authors.affiliation: Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany;
authors.forename: Fabian
authors.initials: F
authors.lastname: Oberle
authors.affiliation: Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany;
authors.forename: Magdalena
authors.initials: M
authors.lastname: Wienken
authors.affiliation: Computational Systems Biology, German Center for Neurodegenerative Diseases, 37077 Göttingen, Germany;
authors.forename: Magali
authors.initials: M
authors.lastname: Hennion
authors.affiliation: Computational Systems Biology, German Center for Neurodegenerative Diseases, 37077 Göttingen, Germany;
authors.forename: Ramon
authors.initials: R
authors.lastname: Vidal
authors.affiliation: Department of Neurophysiology and Cellular Biophysics, Göttingen University, 37073 Göttingen, Germany;
authors.forename: Bettina
authors.initials: B
authors.lastname: Royen
authors.affiliation: Department of Neurophysiology and Cellular Biophysics, Göttingen University, 37073 Göttingen, Germany;
authors.forename: Mihai
authors.initials: M
authors.lastname: Alevra
authors.affiliation: Department of Neurophysiology and Cellular Biophysics, Göttingen University, 37073 Göttingen, Germany;
authors.forename: Detlev
authors.initials: D
authors.lastname: Schild
authors.affiliation: Department of Internal Medicine V, Saarland University, Homburg 66421, Germany;
authors.forename: Robert
authors.initials: R
authors.lastname: Bals
authors.affiliation: Department of Evolutionary Developmental Genetics, Göttingen University, 37077 Göttingen, Germany;
authors.forename: Jürgen
authors.initials: J
authors.lastname: Dönitz
authors.affiliation: Electron Microscopy, Max-Planck-Institute for Biophysical Chemistry, 37077 Göttingen, Germany;
authors.forename: Dietmar
authors.initials: D
authors.lastname: Riedel
authors.affiliation: Computational Systems Biology, German Center for Neurodegenerative Diseases, 37077 Göttingen, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Bonn
authors.affiliation: Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794, USA;
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Takemaru
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA; Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany;
authors.forename: Ute M
authors.initials: UM
authors.lastname: Moll
authors.affiliation: Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany; Clinic for Cardiology and Pneumology, Department of Pneumology, University Medical Center Göttingen, 37099 Göttingen, Germany.
authors.forename: Muriel
authors.initials: M
authors.lastname: Lizé
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D002923:Cilia / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D055786:Gene Knockout Techniques; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology*; D012141:Respiratory Tract Infections / Q000235:genetics / Q000503:physiopathology
chemical_list: D009687:Nuclear Proteins; C454920:delta Np73, mouse
keywords: TAp73; TP73; airways; central transcriptional regulator; motile multiciliogenesis; p73