title: Remodeling of the Inner Hair Cell Microtubule Meshwork in a Mouse Model of Auditory Neuropathy AUNA1.
abstract: Auditory neuropathy 1 (AUNA1) is a form of human deafness resulting from a point mutation in the 5' untranslated region of theDiaphanous homolog 3(DIAPH3) gene. Notably, theDIAPH3mutation leads to the overexpression of the DIAPH3 protein, a formin family member involved in cytoskeleton dynamics. Through study of diap3-overexpressing transgenic (Tg) mice, we examine in further detail the anatomical, functional, and molecular mechanisms underlying AUNA1. We identify diap3 as a component of the hair cells apical pole in wild-type mice. In the diap3-overexpressing Tg mice, which show a progressive threshold shift associated with a defect in inner hair cells (IHCs), the neurotransmitter release and potassium conductances are not affected. Strikingly, the overexpression of diap3 results in a selective and early-onset alteration of the IHC cuticular plate. Molecular dissection of the apical components revealed that the microtubule meshwork first undergoes aberrant targeting into the cuticular plate of Tg IHCs, followed by collapse of the stereociliary bundle, with eventual loss of the IHC capacity to transmit incoming auditory stimuli.
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, University of Montpellier , 34295 Montpellier, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Surel
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, University of Montpellier , 34295 Montpellier, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Guillet
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, University of Montpellier , 34295 Montpellier, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lenoir
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, University of Montpellier , 34295 Montpellier, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bourien
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, University of Montpellier , 34295 Montpellier, France.
authors.forename: Gaston
authors.initials: G
authors.lastname: Sendin
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, University of Montpellier , 34295 Montpellier, France.
authors.forename: Willy
authors.initials: W
authors.lastname: Joly
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, University of Montpellier , 34295 Montpellier, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Delprat
authors.affiliation: Division of Pediatric Otolaryngology, Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health System , Ann Arbor, MI 48109.
authors.forename: Marci M
authors.initials: MM
authors.lastname: Lesperance
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, University of Montpellier , 34295 Montpellier, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Puel
authors.affiliation: Inserm U1051, Institute for Neurosciences of Montpellier, University of Montpellier , 34295 Montpellier, France.
authors.forename: Régis
authors.identifier: 0000-0002-0901-4666
authors.initials: R
authors.lastname: Nouvian
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D057809:HEK293 Cells; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism* / Q000473:pathology; D006313:Hearing Loss, Central / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism* / Q000473:pathology; D009252:NADPH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D017084:Otoacoustic Emissions, Spontaneous / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism / Q000473:pathology
chemical_list: D008869:Microtubule-Associated Proteins; C508552:Dia2 protein, mouse; D009252:NADPH Dehydrogenase; D011188:Potassium; D002118:Calcium
keywords: cochlea; cuticular plate; deafness; diap3; diaphanous