title: Loss of Dishevelleds disrupts planar polarity in ependymal motile cilia and results in hydrocephalus.
abstract: Defects in ependymal (E) cells, which line the ventricle and generate cerebrospinal fluid flow through ciliary beating, can cause hydrocephalus. Dishevelled genes (Dvls) are essential for Wnt signaling, and Dvl2 has been shown to localize to the rootlet of motile cilia. Using the hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) mouse, we show that compound genetic ablation of Dvls causes hydrocephalus. In hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) mutants, E cells differentiated normally, but the intracellular and intercellular rotational alignments of ependymal motile cilia were disrupted. As a consequence, the fluid flow generated by the hGFAP-Cre;Dvl1(-/-);2(flox/flox);3(+/-) E cells was significantly slower than that observed in control mice. Dvls were also required for the proper positioning of motile cilia on the apical surface. Tamoxifen-induced conditional removal of Dvls in adult mice also resulted in defects in intracellular rotational alignment and positioning of ependymal motile cilia. These results suggest that Dvls are continuously required for E cell planar polarity and may prevent 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, CA 94143, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ohata
authors.affiliation: Department of Pediatrics and Institute for Human Genetics, School of Medicine, UCSF, San Francisco, CA 94143, USA; Biomedical Magnetic Resonance Science Unit, Molecular Neuroscience Research Center, Shiga University of Medical Science, Ohtsu, Shiga 520-2192, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Nakatani
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, 46013 Valencia, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Herranz-Pérez
authors.affiliation: UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: JrGang
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Pediatrics and Institute for Human Genetics, School of Medicine, UCSF, San Francisco, CA 94143, USA.
authors.forename: Haim
authors.initials: H
authors.lastname: Belinson
authors.affiliation: Biomedical Magnetic Resonance Science Unit, Molecular Neuroscience Research Center, Shiga University of Medical Science, Ohtsu, Shiga 520-2192, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Inubushi
authors.affiliation: UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Snider
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, 46013 Valencia, Spain.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: García-Verdugo
authors.affiliation: Department of Pediatrics and Institute for Human Genetics, School of Medicine, UCSF, San Francisco, CA 94143, USA; Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: ajw168@case.edu.
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
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, CA 94143, USA. Electronic address: abuylla@stemcell.ucsf.edu.
authors.forename: Arturo
authors.initials: A
authors.lastname: Alvarez-Buylla
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology*; D002923:Cilia / Q000235:genetics / Q000473:pathology*; D000072261:Dishevelled Proteins; D004805:Ependyma / Q000473:pathology*; D006849:Hydrocephalus / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606578:DVL1 protein, human; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; C000606582:Dvl2 protein, mouse; D010750:Phosphoproteins