title: Individual USH2 proteins make distinct contributions to the ankle link complex during development of the mouse cochlear stereociliary bundle.
abstract: Usher syndrome (USH) is the leading cause of inherited deaf-blindness, with type 2 (USH2) being the most common clinical form. Studies suggest that proteins encoded by USH2 causative genes assemble into the ankle link complex (ALC) at the hair cell stereociliary bundle; however, little is known about the in vivo assembly and function of this complex. Using various USH2 mutant mice, we showed by immunofluorescence that USH2 proteins play different roles in cochlear ALC assembly, with G protein-coupled receptor 98 being the most important protein. Complex assembly likely occurs at the stereociliary bundle but not along the protein transport route in the cell body. Stereociliary morphological defects in USH2 mutant mice suggest roles for the ALC in regulating inner hair cell stereociliary growth and differentiation as well as outer hair cell stereociliary rigidity and organization during development. These roles are unique from the bundle cohesion role of Usher syndrome type 1 protein complexes. Loss of individual USH2 gene expressions leads to variable morphological and functional consequences, correlating with the severity of ALC disruption. This finding suggests a potential genotype-phenotype correlation in USH2 patients. In summary, this study provides novel insights into the molecular mechanism underlying cochlear stereociliary bundle development and hearing loss pathogenesis of various USH2 subtypes. Our thorough phenotypical characterization of USH2 mouse models is essential for future use of these animal models in therapeutic development.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA.
authors.forename: Junhuang
authors.initials: J
authors.lastname: Zou
authors.affiliation: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA, Department of Neurobiology and Anatomy, University of Utah, 20 North 1900 East, Salt Lake City, UT 84132, USA.
authors.forename: Pranav D
authors.initials: PD
authors.lastname: Mathur
authors.affiliation: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA.
authors.forename: Tihua
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Division of Otolaryngology, Department of Surgery, University of Utah, 30 North 1900 East, Salt Lake City, UT 84132, USA and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Communication Sciences and Disorders, University of Utah, 390 South 1530 East, Salt Lake City, UT 84112, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Almishaal
authors.affiliation: Division of Otolaryngology, Department of Surgery, University of Utah, 30 North 1900 East, Salt Lake City, UT 84132, USA and.
authors.forename: Albert H
authors.initials: AH
authors.lastname: Park
authors.affiliation: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA, Department of Neurobiology and Anatomy, University of Utah, 20 North 1900 East, Salt Lake City, UT 84132, USA, Division of Otolaryngology, Department of Surgery, University of Utah, 30 North 1900 East, Salt Lake City, UT 84132, USA and jun.yang@hsc.utah.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003051:Cochlea / Q000196:embryology* / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006198:Hair Cells, Auditory; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009024:Morphogenesis / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D052245:Usher Syndromes / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D002352:Carrier Proteins; D016326:Extracellular Matrix Proteins; D008565:Membrane Proteins; D043562:Receptors, G-Protein-Coupled; C485949:Adgrv1 protein, mouse; C000594656:PDZD7 protein, mouse; C491810:Ush2a protein, mouse; C477218:Whrn protein, mouse