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Cell Rep ; 14(10): 2289-300, 2016 Mar 15.
Article in English | MEDLINE | ID: mdl-26947080

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.


Subject(s)
Cilia/metabolism , Forkhead Transcription Factors/metabolism , Gene Regulatory Networks , Lung/metabolism , Tumor Protein p73/metabolism , Animals , Bronchioles/metabolism , Bronchioles/pathology , Cell Differentiation , Cells, Cultured , Cilia/pathology , Epithelial Cells/cytology , Epithelial Cells/metabolism , Epithelium/metabolism , Epithelium/pathology , Female , Forkhead Transcription Factors/genetics , Lung/cytology , 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
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