title: Mechanosensory Genes Pkd1 and Pkd2 Contribute to the Planar Polarization of Brain Ventricular Epithelium.
abstract: Directional beating of ependymal (E) cells' cilia in the walls of the ventricles in the brain is essential for proper CSF flow. E cells display two forms of planar cell polarity (PCP): rotational polarity of individual cilium and translational polarity (asymmetric positioning of cilia in the apical area). The orientation of individual E cells varies according to their location in the ventricular wall (location-specific PCP). It has been hypothesized that hydrodynamic forces on the apical surface of radial glia cells (RGCs), the embryonic precursors of E cells, could guide location-specific PCP in the ventricular epithelium. However, the detection mechanisms for these hydrodynamic forces have not been identified. Here, we show that the mechanosensory proteins polycystic kidney disease 1 (Pkd1) and Pkd2 are present in primary cilia of RGCs. Ablation of Pkd1 or Pkd2 in Nestin-Cre;Pkd1(flox/flox) or Nestin-Cre;Pkd2(flox/flox) mice, affected PCP development in RGCs and E cells. Early shear forces on the ventricular epithelium may activate Pkd1 and Pkd2 in primary cilia of RGCs to properly polarize RGCs and E cells. Consistently, Pkd1, Pkd2, or primary cilia on RGCs were required for the proper asymmetric localization of the PCP protein Vangl2 in E cells' apical area. Analyses of single- and double-heterozygous mutants for Pkd1 and/or Vangl2 suggest that these genes function in the same pathway to establish E cells' PCP. We conclude that Pkd1 and Pkd2 mechanosensory proteins contribute to the development of brain PCP and prevention of hydrocephalus.
  
  
  CONCLUSIONS
  This study identifies key molecules in the development of planar cell polarity (PCP) in the brain and prevention of hydrocephalus. Multiciliated ependymal (E) cells within the brain ventricular epithelium generate CSF flow through ciliary beating. E cells display location-specific PCP in the orientation and asymmetric positioning of their cilia. Defects in this PCP can result in hydrocephalus. Hydrodynamic forces on radial glial cells (RGCs), the embryonic progenitors of E cells, have been suggested to guide PCP. We show that the mechanosensory proteins Pkd1 and Pkd2 localize to primary cilia in RGCs, and their ablation disrupts the development of PCP in E cells. Early shear forces on RGCs may activate Pkd1 and Pkd2 in RGCs' primary cilia to properly orient E cells. This study identifies key molecules in the development of brain PCP and prevention of hydrocephalus.
authors.affiliation: Department of Neurological Surgery, and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, California 94143, ohata@mol.f.u-tokyo.ac.jp ABuylla@stemcell.ucsf.edu.
authors.forename: Shinya
authors.identifier: http://orcid.org/0000-0003-4333-4433
authors.initials: S
authors.lastname: Ohata
authors.affiliation: Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universidad de Valencia, CIBERNED, 46980 Valencia, Spain, Unidad Mixta de Esclerosis Múltiple y Neurorregeneración, IIS Hospital La Fe, 46026 Valencia, Spain.
authors.forename: Vicente
authors.identifier: http://orcid.org/0000-0002-1969-1214
authors.initials: V
authors.lastname: Herranz-Pérez
authors.affiliation: Biomedical MR Science Division, Shiga University of Medical Science, Ohtsu, Shiga 520-2192, Japan, and.
authors.forename: Jin
authors.initials: J
authors.lastname: Nakatani
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Alessandra
authors.identifier: http://orcid.org/0000-0002-4704-4006
authors.initials: A
authors.lastname: Boletta
authors.affiliation: Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universidad de Valencia, CIBERNED, 46980 Valencia, Spain, Unidad Mixta de Esclerosis Múltiple y Neurorregeneración, IIS Hospital La Fe, 46026 Valencia, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: García-Verdugo
authors.affiliation: Department of Neurological Surgery, and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, California 94143, ohata@mol.f.u-tokyo.ac.jp ABuylla@stemcell.ucsf.edu.
authors.forename: Arturo
authors.initials: A
authors.lastname: Álvarez-Buylla
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000235:genetics*; D002552:Cerebral Ventricles / Q000378:metabolism*; D002923:Cilia / Q000378:metabolism*; D004805:Ependyma / Q000166:cytology / Q000378:metabolism; D063928:Ependymoglial Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D050396:TRPP Cation Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D050396:TRPP Cation Channels
keywords: cilia; ependymal cell; epithelium; neural stem cell; planar cell polarity; polycystin