title: ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells.
abstract: In the mammalian inner ear, bicellular and tricellular tight junctions (tTJs) seal the paracellular space between epithelial cells. Tricellulin and immunoglobulin-like (Ig-like) domain containing receptor 1 (ILDR1, also referred to as angulin-2) localize to tTJs of the sensory and non-sensory epithelia in the organ of Corti and vestibular end organs. Recessive mutations of TRIC (DFNB49) encoding tricellulin and ILDR1 (DFNB42) cause human nonsyndromic deafness. However, the pathophysiology of DFNB42 deafness remains unknown. ILDR1 was recently reported to be a lipoprotein receptor mediating the secretion of the fat-stimulated cholecystokinin (CCK) hormone in the small intestine, while ILDR1 in EpH4 mouse mammary epithelial cells in vitro was shown to recruit tricellulin to tTJs. Here we show that two different mouse Ildr1 mutant alleles have early-onset severe deafness associated with a rapid degeneration of cochlear hair cells (HCs) but have a normal endocochlear potential. ILDR1 is not required for recruitment of tricellulin to tTJs in the cochlea in vivo; however, tricellulin becomes mislocalized in the inner ear sensory epithelia of ILDR1 null mice after the first postnatal week. As revealed by freeze-fracture electron microscopy, ILDR1 contributes to the ultrastructure of inner ear tTJs. Taken together, our data provide insight into the pathophysiology of human DFNB42 deafness and demonstrate that ILDR1 is crucial for normal hearing by maintaining the structural and functional integrity of tTJs, which are critical for the survival of auditory neurosensory HCs.
authors.affiliation: National Institute on Deafness and Other Communication Disorders, Section on Human Genetics.
authors.forename: Eva L
authors.initials: EL
authors.lastname: Morozko
authors.affiliation: National Institute on Deafness and Other Communication Disorders, Molecular Biology and Genetics Section.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nishio
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Ingham
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Chandra
authors.affiliation: National Institute on Deafness and Other Communication Disorders, Mouse Auditory Testing Core Facility, National Institutes of Health, Bethesda, MD 20892-3729, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Fitzgerald
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: Martelletti
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm 89081, Germany.
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
authors.affiliation: National Institute on Deafness and Other Communication Disorders, Section on Human Genetics.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wilson
authors.affiliation: National Institute on Deafness and Other Communication Disorders, Section on Human Genetics.
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Riordan
authors.affiliation: Anatomy and Physiology Department, Kansas State University, Manhattan, KS 66506-5802, USA and.
authors.forename: Philine
authors.initials: P
authors.lastname: Wangemann
authors.affiliation: Centre for Auditory Research, University College London, London WC1X 8EE, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Forge
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.
authors.forename: Karen P
authors.initials: KP
authors.lastname: Steel
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Rodger A
authors.initials: RA
authors.lastname: Liddle
authors.affiliation: National Institute on Deafness and Other Communication Disorders, Section on Human Genetics.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
authors.affiliation: National Institute on Deafness and Other Communication Disorders, Section on Human Genetics belyants@nidcd.nih.gov.
authors.forename: Inna A
authors.initials: IA
authors.lastname: Belyantseva
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000473:pathology*; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D062794:MARVEL Domain Containing 2 Protein / Q000378:metabolism; D051379:Mice; D009154:Mutation; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology*
chemical_list: C583885:Ildr1 protein, mouse; D062794:MARVEL Domain Containing 2 Protein; C508309:Marveld2 protein, mouse; D011956:Receptors, Cell Surface