p73 and FoxJ1: Programming Multiciliated Epithelia.

The mysteriously diverse phenotypes in mice lacking the p53 homolog p73 are recently unified by new analysis showing p73 is required for formation of multiciliated epithelia. p73 directly activates FoxJ1, the central transcriptional driver for multiciliation, and induces a host of genes critical for ciliogenesis.

Jackson PK ，Attardi LD 《-》

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

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.

Marshall CB ，Mays DJ ，Beeler JS ，Rosenbluth JM ，Boyd KL ，Santos Guasch GL ，Shaver TM ，Tang LJ ，Liu Q ，Shyr Y ，Venters BJ ，Magnuson MA ，Pietenpol JA ... -  《Cell Reports》

GemC1 governs multiciliogenesis through direct interaction with and transcriptional regulation of p73.

A distinct combination of transcription factors elicits the acquisition of a specific fate and the initiation of a differentiation program. Multiciliated cells (MCCs) are a specialized type of epithelial cells that possess dozens of motile cilia on their apical surface. Defects in cilia function have been associated with ciliopathies that affect many organs, including brain and airway epithelium. Here we show that the geminin coiled-coil domain-containing protein 1 GemC1 (also known as Lynkeas) regulates the transcriptional activation of p73, a transcription factor central to multiciliogenesis. Moreover, we show that GemC1 acts in a trimeric complex with transcription factor E2F5 and tumor protein p73 (officially known as TP73), and that this complex is important for the activation of the p73 promoter. We also provide in vivo evidence that GemC1 is necessary for p73 expression in different multiciliated epithelia. We further show that GemC1 regulates multiciliogenesis through the control of chromatin organization, and the epigenetic marks/tags of p73 and Foxj1. Our results highlight novel signaling cues involved in the commitment program of MCCs across species and tissues.This article has an associated First Person interview with the first author of the paper.

Lalioti ME ，Arbi M ，Loukas I ，Kaplani K ，Kalogeropoulou A ，Lokka G ，Kyrousi C ，Mizi A ，Georgomanolis T ，Josipovic N ，Gkikas D ，Benes V ，Politis PK ，Papantonis A ，Lygerou Z ，Taraviras S ... -  《-》

p73 is required for appropriate BMP-induced mesenchymal-to-epithelial transition during somatic cell reprogramming.

Martin-Lopez M ，Maeso-Alonso L ，Fuertes-Alvarez S ，Balboa D ，Rodríguez-Cortez V ，Weltner J ，Diez-Prieto I ，Davis A ，Wu Y ，Otonkoski T ，Flores ER ，Menéndez P ，Marques MM ，Marin MC ... -  《Cell Death & Disease》

p73 regulates epidermal wound healing and induced keratinocyte programming.

Beeler JS ，Marshall CB ，Gonzalez-Ericsson PI ，Shaver TM ，Santos Guasch GL ，Lea ST ，Johnson KN ，Jin H ，Venters BJ ，Sanders ME ，Pietenpol JA ... -  《PLoS One》