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Genes Dev. 2016 Jun 1;30(11):1300-12. doi: 10.1101/gad.279836.116. Epub 2016 Jun 2.

TAp73 is a central transcriptional regulator of airway multiciliogenesis.

Author information

1
Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA;
2
Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany;
3
Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794, USA;
4
Department of Internal Medicine V, Saarland University, Homburg 66421, Germany;
5
Computational Systems Biology, German Center for Neurodegenerative Diseases, 37077 Göttingen, Germany;
6
Department of Neurophysiology and Cellular Biophysics, Göttingen University, 37073 Göttingen, Germany;
7
Department of Evolutionary Developmental Genetics, Göttingen University, 37077 Göttingen, Germany;
8
Electron Microscopy, Max-Planck-Institute for Biophysical Chemistry, 37077 Göttingen, Germany;
9
Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA; Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany;
10
Institute of Molecular Oncology, Göttingen University, 37077 Göttingen, Germany; Clinic for Cardiology and Pneumology, Department of Pneumology, University Medical Center Göttingen, 37099 Göttingen, Germany.

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.

KEYWORDS:

TAp73; TP73; airways; central transcriptional regulator; motile multiciliogenesis; p73

PMID:
27257214
PMCID:
PMC4911929
DOI:
10.1101/gad.279836.116
[Indexed for MEDLINE]
Free PMC Article

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