title: The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1.
abstract: Mutations in the DFNB31 gene encoding the PDZ scaffold protein whirlin are causative for hearing loss in man and mouse. Whirlin is known to be essential for the elongation process of the stereocilia of sensory hair cells in the inner ear, though its complete spatial and temporal expression patterns remained elusive. Here, we demonstrate that, in embryonic development, the gene is not only expressed in the inner ear, but also in the developing brain and the retina. Various isoforms of whirlin are widely and differentially expressed, and we provide evidence that whirlin directly associates with USH2A isoform b and VLGR1b, two proteins that we previously reported to be part of the Usher protein interactome. These proteins co-localize with whirlin at the synaptic regions of both photoreceptor cells and outer hair cells in the cochlea. These findings indicate that whirlin is part of a macromolecular PDZ protein scaffold that functions in the organization of the pre- and/or postsynaptic side of photoreceptor and hair cell synapses. Whirlin might be involved in synaptic adhesion through interaction with USH2A and VLGR1b as well as in synaptic development as suggested by its spatial and temporal expression patterns. In addition, we demonstrate that whirlin, USH2A and Vlgr1b co-localize at the connecting cilium and the outer limiting membrane of photoreceptor cells and in spiral ganglion neurons of the inner ear. Our data show that whirlin is connected to the dynamic Usher protein interactome and indicate that whirlin has a pleiotropic function in both the retina and the inner ear.
authors.affiliation: Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Erwin
authors.initials: E
authors.lastname: van Wijk
authors.forename: Bert
authors.initials: B
authors.lastname: van der Zwaag
authors.forename: Theo
authors.initials: T
authors.lastname: Peters
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zimmermann
authors.forename: Heleen
authors.initials: H
authors.lastname: Te Brinke
authors.forename: Ferry F J
authors.initials: FF
authors.lastname: Kersten
authors.forename: Tina
authors.initials: T
authors.lastname: Märker
authors.forename: Elena
authors.initials: E
authors.lastname: Aller
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.forename: Cor W R J
authors.initials: CW
authors.lastname: Cremers
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.forename: Marlies
authors.initials: M
authors.lastname: Knipper
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003051:Cochlea / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006168:Guinea Pigs; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D016326:Extracellular Matrix Proteins; D008565:Membrane Proteins; D043562:Receptors, G-Protein-Coupled; C485949:Adgrv1 protein, mouse; C491810:Ush2a protein, mouse; C491809:Ush2a protein, rat; C477219:WHRN protein, human; C477218:Whrn protein, mouse