학술논문
p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton.
Document Type
Academic Journal
Author
Fuertes-Alvarez S; Instituto de Biomedicina (IBIOMED) and Departamento de Biología Molecular, Universidad de León, Campus de Vegazana, 24071, León, Spain.; Maeso-Alonso L; Instituto de Biomedicina (IBIOMED) and Departamento de Biología Molecular, Universidad de León, Campus de Vegazana, 24071, León, Spain.; Villoch-Fernandez J; Instituto de Biomedicina (IBIOMED) and Departamento de Biología Molecular, Universidad de León, Campus de Vegazana, 24071, León, Spain.; Wildung M; Molecular and Experimental Pneumology Group, Clinic for Cardiology and Pneumology, University Medical Center, 37077, Göttingen, Germany.; Institute of Molecular Oncology, Clinic for Cardiology and Pneumology, Department of Pneumology, University Medical Center Göttingen, Göttingen, Germany.; Martin-Lopez M; Instituto de Biomedicina (IBIOMED) and Departamento de Biología Molecular, Universidad de León, Campus de Vegazana, 24071, León, Spain.; Marshall C; Department of Biochemistry and Vanderbilt-Ingram Cancer Center, Vanderbilt University and Vanderbilt University Medical Center, Nashville, TN, 37232, USA.; Villena-Cortes AJ; Instituto de Biomedicina (IBIOMED) and Departamento de Biología Molecular, Universidad de León, Campus de Vegazana, 24071, León, Spain.; Diez-Prieto I; Departamento de Medicina, Cirugía y Anatomía Veterinaria, Universidad de León, Campus de Vegazana, 24071, León, Spain.; Pietenpol JA; Department of Biochemistry and Vanderbilt-Ingram Cancer Center, Vanderbilt University and Vanderbilt University Medical Center, Nashville, TN, 37232, USA.; Tissir F; Developmental Neurobiology, Institute of Neuroscience, Universite Catholique de Louvain, Avenue E. Mounier, 73, Box B1.73.16, B1200, Brussels, Belgium.; Lizé M; Molecular and Experimental Pneumology Group, Clinic for Cardiology and Pneumology, University Medical Center, 37077, Göttingen, Germany.; Institute of Molecular Oncology, Clinic for Cardiology and Pneumology, Department of Pneumology, University Medical Center Göttingen, Göttingen, Germany.; Marques MM; Instituto de Desarrollo Ganadero (INDEGSAL) and Departamento de Producción Animal, Universidad de León, Campus de Vegazana, 24071, León, Spain.; Marin MC; Instituto de Biomedicina (IBIOMED) and Departamento de Biología Molecular, Universidad de León, Campus de Vegazana, 24071, León, Spain. carmen.marin@unileon.es.
Source
Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE
Subject
Language
English
Abstract
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.