title: The PDZ Protein Na+/H+ Exchanger Regulatory Factor-1 (NHERF1) Regulates Planar Cell Polarity and Motile Cilia Organization.
abstract: Directional flow of the cerebrospinal fluid requires coordinated movement of the motile cilia of the ependymal epithelium that lines the cerebral ventricles. Here we report that mice lacking the Na+/H+ Exchanger Regulatory Factor 1 (NHERF1/Slc9a3r1, also known as EBP50) develop profound communicating hydrocephalus associated with fewer and disorganized ependymal cilia. Knockdown of NHERF1/slc9a3r1 in zebrafish embryos also causes severe hydrocephalus of the hindbrain and impaired ciliogenesis in the otic vesicle. Ultrastructural analysis did not reveal defects in the shape or organization of individual cilia. Similar phenotypes have been described in animals with deficiencies in Wnt signaling and the Planar Cell Polarity (PCP) pathway. We show that NHERF1 binds the PCP core genes Frizzled (Fzd) and Vangl. We further show that NHERF1 assembles a ternary complex with Fzd4 and Vangl2 and promotes translocation of Vangl2 to the plasma membrane, in particular to the apical surface of ependymal cells. Taken together, these results strongly support an important role for NHERF1 in the regulation of PCP signaling and the development of functional motile cilia.
authors.affiliation: Laboratory for GPCR Biology, Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Anny Caceres
authors.initials: AC
authors.lastname: Treat
authors.affiliation: Laboratory for GPCR Biology, Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.|Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: David S
authors.initials: DS
authors.lastname: Wheeler
authors.affiliation: Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Tsang
authors.affiliation: Laboratory for GPCR Biology, Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.|Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Friedman
authors.affiliation: Laboratory for GPCR Biology, Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Romero
mesh_terms: D000818:Animals; D016466:CHO Cells; D016764:Cell Polarity; D002923:Cilia / Q000502:physiology / Q000648:ultrastructure*; D003412:Cricetulus; D055785:Gene Knockdown Techniques; D006849:Hydrocephalus / Q000235:genetics* / Q000662:veterinary; D051379:Mice; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D015027:Zebrafish
chemical_list: D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor