title: Role for a novel Usher protein complex in hair cell synaptic maturation.
abstract: The molecular mechanisms underlying hair cell synaptic maturation are not well understood. Cadherin-23 (CDH23), protocadherin-15 (PCDH15) and the very large G-protein coupled receptor 1 (VLGR1) have been implicated in the development of cochlear hair cell stereocilia, while clarin-1 has been suggested to also play a role in synaptogenesis. Mutations in CDH23, PCDH15, VLGR1 and clarin-1 cause Usher syndrome, characterized by congenital deafness, vestibular dysfunction and retinitis pigmentosa. Here we show developmental expression of these Usher proteins in afferent spiral ganglion neurons and hair cell synapses. We identify a novel synaptic Usher complex comprised of clarin-1 and specific isoforms of CDH23, PCDH15 and VLGR1. To establish the in vivo relevance of this complex, we performed morphological and quantitative analysis of the neuronal fibers and their synapses in the Clrn1-/- mouse, which was generated by incomplete deletion of the gene. These mice showed a delay in neuronal/synaptic maturation by both immunostaining and electron microscopy. Analysis of the ribbon synapses in Ames waltzer(av3J) mice also suggests a delay in hair cell synaptogenesis. Collectively, these results show that, in addition to the well documented role for Usher proteins in stereocilia development, Usher protein complexes comprised of specific protein isoforms likely function in synaptic maturation as well.
authors.affiliation: Boys Town National Research Hospital, Omaha, Nebraska, United States of America.
authors.forename: Marisa
authors.initials: M
authors.lastname: Zallocchi
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Meehan
authors.forename: Duane
authors.initials: D
authors.lastname: Delimont
authors.forename: Joseph
authors.initials: J
authors.lastname: Rutledge
authors.forename: Michael Anne
authors.initials: MA
authors.lastname: Gratton
authors.forename: John
authors.initials: J
authors.lastname: Flannery
authors.forename: Dominic
authors.initials: D
authors.lastname: Cosgrove
mesh_terms: D000327:Adsorption; D000818:Animals; D000906:Antibodies / Q000276:immunology; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000378:metabolism*; D002460:Cell Line; D016764:Cell Polarity; D055785:Gene Knockdown Techniques; D006198:Hair Cells, Auditory / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D046912:Multiprotein Complexes / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D000906:Antibodies; D000070585:Cadherin Related Proteins; D015820:Cadherins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D020033:Protein Isoforms; D011498:Protein Precursors; D043562:Receptors, G-Protein-Coupled; C418976:CDHR15 protein, mouse; C499091:Cdh23 protein, mouse; C512668:Clrn1 protein, mouse; C485949:Adgrv1 protein, mouse