p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network

• Published in: Cell reports (Cambridge) Vol. 14; no. 10; pp. 2289 - 2300
• Main Authors: Marshall, Clayton B., Mays, Deborah J., Beeler, J. Scott, Rosenbluth, Jennifer M., Boyd, Kelli L., Santos Guasch, Gabriela L., Shaver, Timothy M., Tang, Lucy J., Liu, Qi, Shyr, Yu, Venters, Bryan J., Magnuson, Mark A., Pietenpol, Jennifer A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-03-2016; Elsevier
• Subjects: Animals; Bronchioles - metabolism; Bronchioles - pathology; Cell Differentiation; Cells, Cultured; Cilia - metabolism; Cilia - pathology; Epithelial Cells - cytology; Epithelial Cells - metabolism; Epithelium - metabolism; Epithelium - pathology; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Regulatory Networks; Lung - cytology; Lung - metabolism; Lung - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Phosphoproteins - deficiency; Phosphoproteins - genetics; Phosphoproteins - metabolism; RNA Interference; Sequence Analysis, RNA; Trachea - metabolism; Trachea - pathology; Trans-Activators - deficiency; Trans-Activators - genetics; Trans-Activators - metabolism; Transcriptome; Tumor Protein p73 - deficiency; Tumor Protein p73 - genetics; Tumor Protein p73 - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.02.035

We report that p73 is expressed in multiciliated cells (MCCs), is required for MCC differentiation, and directly regulates transcriptional modulators of multiciliogenesis. Loss of ciliary biogenesis provides a unifying mechanism for many phenotypes observed in p73 knockout mice including hydrocephalus; hippocampal dysgenesis; sterility; and chronic inflammation/infection of lung, middle ear, and sinus. Through p73 and p63 ChIP-seq using murine tracheal cells, we identified over 100 putative p73 target genes that regulate MCC differentiation and homeostasis. We validated Foxj1, a transcriptional regulator of multiciliogenesis, and many other cilia-associated genes as direct target genes of p73 and p63. We show p73 and p63 are co-expressed in a subset of basal cells and suggest that p73 marks these cells for MCC differentiation. In summary, p73 is essential for MCC differentiation, functions as a critical regulator of a transcriptome required for MCC differentiation, and, like p63, has an essential role in development of tissues.
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•p73 is required for murine MCC differentiation•MCC loss provides a unifying biological defect for phenotypes in p73−/− mice•p73 binds to the genome in proximity to 105 cilia-associated genes, including Foxj1•p73 directly regulates and is required for Foxj1 expression
Using a p73-deficient mouse model, Marshall et al. show that p73 is required for MCC differentiation. ChIP-seq of murine tracheal cells reveals many p73 target genes that regulate MCC differentiation. Lack of expression of key transcriptional regulators of ciliogenesis provides a mechanistic basis for the multiple defects in p73-deficient mice.