title: p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network.
abstract: 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.
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Clayton B
authors.initials: CB
authors.lastname: Marshall
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Mays
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Beeler
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Rosenbluth
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Gabriela L
authors.initials: GL
authors.lastname: Santos Guasch
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Shaver
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Tang
authors.affiliation: Center for Quantitative Sciences, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA; Center for Quantitative Sciences, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Venters
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: j.pietenpol@vanderbilt.edu.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pietenpol
mesh_terms: D000818:Animals; D055745:Bronchioles / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053263:Gene Regulatory Networks; D008168:Lung / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D017423:Sequence Analysis, RNA; D014132:Trachea / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D000072160:Tumor Protein p73 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C481963:FOXJ1 protein, mouse; D051858:Forkhead Transcription Factors; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D000072160:Tumor Protein p73