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

Publication date: Available online 3 March 2016
Source:Cell Reports
Author(s): Clayton B. Marshall, Deborah J. Mays, J. Scott Beeler, Jennifer M. Rosenbluth, Kelli L. Boyd, Gabriela L. Santos Guasch, Timothy M. Shaver, Lucy J. Tang, Qi Liu, Yu Shyr, Bryan J. Venters, Mark A. Magnuson, Jennifer A. Pietenpol
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.

Graphical abstract

Teaser

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.


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