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p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton.

Fuertes-Alvarez S, Maeso-Alonso L, Villoch-Fernandez J, Wildung M, Martin-Lopez M, Marshall C, Villena-Cortes AJ, Diez-Prieto I, Pietenpol JA, Tissir F, Lizé M, Marques MM, Marin MC
Cell Death Dis. 2018 9 (12): 1183

PMID: 30518789 · PMCID: PMC6281643 · DOI:10.1038/s41419-018-1205-6

Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct cerebrospinal fluid circulation. Thus, PCP disruption results in ciliopathies and hydrocephalus. PCP establishment depends on the polarization of cytoskeleton and requires the asymmetric localization of core and global regulatory modules, including membrane proteins like Vangl1/2 or Frizzled. We analyzed the subcellular localization of select proteins that make up these modules in ependymal cells and the effect of Trp73 loss on their localization. We identify a novel function of the Trp73 tumor suppressor gene, the TAp73 isoform in particular, as an essential regulator of PCP through the modulation of actin and microtubule cytoskeleton dynamics, demonstrating that Trp73 is a key player in the organization of ependymal ciliated epithelia. Mechanistically, we show that p73 regulates translational PCP and actin dynamics through TAp73-dependent modulation of non-musclemyosin-II activity. In addition, TAp73 is required for the asymmetric localization of PCP-core and global signaling modules and regulates polarized microtubule dynamics, which in turn set up the rotational PCP. Therefore, TAp73 modulates, directly and/or indirectly, transcriptional programs regulating actin and microtubules dynamics and Golgi organization signaling pathways. These results shed light into the mechanism of ependymal cell planar polarization and reveal p73 as an epithelial architect during development regulating the cellular cytoskeleton.

MeSH Terms (24)

Animals Carrier Proteins Cell Polarity Cilia Cytoskeleton Ependyma Female Frizzled Receptors Gene Expression Regulation Gene Ontology HCT116 Cells Humans Male Membrane Proteins Mice Mice, Inbred C57BL Mice, Knockout Microtubules Molecular Sequence Annotation Nerve Tissue Proteins Nonmuscle Myosin Type IIA Pluripotent Stem Cells Signal Transduction Tumor Protein p73

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