TAp73 is a central transcriptional regulator of airway multiciliogenesis
- Alice Nemajerova1,
- Daniela Kramer2,10,
- Saul S. Siller3,10,
- Christian Herr4,10,
- Orr Shomroni5,
- Tonatiuh Pena5,
- Cristina Gallinas Suazo2,
- Katharina Glaser2,
- Merit Wildung2,
- Henrik Steffen2,
- Anusha Sriraman2,
- Fabian Oberle2,
- Magdalena Wienken2,
- Magali Hennion5,
- Ramon Vidal5,
- Bettina Royen6,
- Mihai Alevra6,
- Detlev Schild6,
- Robert Bals4,
- Jürgen Dönitz7,
- Dietmar Riedel8,
- Stefan Bonn5,
- Ken-Ichi Takemaru3,
- Ute M. Moll1,2 and
- Muriel Lizé2,9
- 1Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA;
- 2Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany;
- 3Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794, USA;
- 4Department of Internal Medicine V, Saarland University, Homburg 66421, Germany;
- 5Computational Systems Biology, German Center for Neurodegenerative Diseases, 37077 Göttingen, Germany;
- 6Department of Neurophysiology and Cellular Biophysics, Göttingen University, 37073 Göttingen, Germany;
- 7Department of Evolutionary Developmental Genetics, Göttingen University, 37077 Göttingen, Germany;
- 8Electron Microscopy, Max-Planck-Institute for Biophysical Chemistry, 37077 Göttingen, Germany;
- 9Clinic for Cardiology and Pneumology, Department of Pneumology, University Medical Center Göttingen, 37099 Göttingen, Germany
- Corresponding authors: ute.moll{at}stonybrook.edu, alice.nemajerova{at}stonybrook.edu, mlize{at}gwdg.de
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↵10 These authors contributed equally to this work.
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.279836.116.
- Received February 21, 2016.
- Accepted May 2, 2016.
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