ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Oscar Diaz-Horta; Clemer Abad; Levent Sennaroglu; Joseph Foster, 2nd; Alexandra DeSmidt; Guney Bademci; Suna Tokgoz-Yilmaz; Duygu Duman; F Basak Cengiz; M'hamed Grati; Suat Fitoz; Xue Z Liu; Amjad Farooq; Faiqa Imtiaz; Benjamin B Currall; Cynthia Casson Morton; Michiru Nishita; Yasuhiro Minami; Zhongmin Lu; Katherina Walz; Mustafa Tekin

doi:10.1073/pnas.1522512113

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ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Journal article

Open access

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Oscar Diaz-Horta, Clemer Abad, Levent Sennaroglu, Joseph Foster, 2nd, Alexandra DeSmidt, Guney Bademci, Suna Tokgoz-Yilmaz, Duygu Duman, F Basak Cengiz, M'hamed Grati, …

Proceedings of the National Academy of Sciences - PNAS, Vol.113(21), pp.5993-5998

2016-05-24

DOI: https://doi.org/10.1073/pnas.1522512113

PMCID: PMC4889368

PMID: 27162350

Abstract

Cell Line

Hair Cells, Auditory - metabolism

Hair Cells, Auditory - pathology

Hearing Loss, Sensorineural - metabolism

Wnt-5a Protein - genetics

Receptor Tyrosine Kinase-like Orphan Receptors - metabolism

Humans

Axons - metabolism

Hearing Loss, Sensorineural - pathology

Hearing Loss, Sensorineural - genetics

Spiral Ganglion - metabolism

Wnt-5a Protein - metabolism

Animals

Mice, Mutant Strains

Axons - pathology

Spiral Ganglion - pathology

Receptor Tyrosine Kinase-like Orphan Receptors - genetics

Mice

Mutation

Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell-neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicity-matched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.150 Hearing Loss; 1.150.421 Cochlea
Web Of Science research areas: Multidisciplinary Sciences
ESI research areas: Molecular Biology & Genetics

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Title: ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice
Creators: Oscar Diaz-Horta - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136
Clemer Abad - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136
Levent Sennaroglu - Department of Otolaryngology, Hacettepe University School of Medicine, Ankara, 06100, Turkey
Joseph Foster, 2nd - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136
Alexandra DeSmidt - Department of Biology, University of Miami, Miami, FL 33146
Guney Bademci - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136
Suna Tokgoz-Yilmaz - Department of Otolaryngology, Hacettepe University School of Medicine, Ankara, 06100, Turkey
Duygu Duman - Division of Pediatric Genetics, Ankara University School of Medicine, Ankara, 06100, Turkey
F Basak Cengiz - Division of Pediatric Genetics, Ankara University School of Medicine, Ankara, 06100, Turkey
M'hamed Grati - Department of Otolaryngology, Miller School of Medicine, University of Miami, Miami, FL 33136
Suat Fitoz - Department of Radiology, Ankara University School of Medicine, Ankara, 06100, Turkey
Xue Z Liu - Department of Otolaryngology, Miller School of Medicine, University of Miami, Miami, FL 33136
Amjad Farooq - Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136
Faiqa Imtiaz - Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia
Benjamin B Currall - Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115
Cynthia Casson Morton - Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Manchester Academic Health Science Center, University of Manchester, Manchester M13 9NT, United Kingdom
Michiru Nishita - Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, 650-0017, Japan
Yasuhiro Minami - Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, 650-0017, Japan
Zhongmin Lu - Department of Biology, University of Miami, Miami, FL 33146
Katherina Walz - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136
Mustafa Tekin - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136; Department of Otolaryngology, Miller School of Medicine, University of Miami, Miami, FL 33136; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136 mtekin@miami.edu
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.113(21), pp.5993-5998
Publisher: United States
Grant note: R21 DC009879 / NIDCD NIH HHS R01 DC012115 / NIDCD NIH HHS R01 DC005575 / NIDCD NIH HHS R01 DC003402 / NIDCD NIH HHS R01 GM083897 / NIGMS NIH HHS F32 DC012466 / NIDCD NIH HHS R01 DC012836 / NIDCD NIH HHS R01 DC009645 / NIDCD NIH HHS
Academic Unit: UMMG Department of Otolaryngology; UMMG Dept of Human Genetics - Clinical and Translational Genetics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation); A&S - Biology; Miller School of Medicine; College of A&S; Biochemistry & Molecular Biology Research; John P. Hussman Institute for Human Genomics
Language: English
Resource Type: Journal article
PMID: 27162350
PMCID: PMC4889368
Record Identifier: 991031560470802976