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 Ii, 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 Morton, Michiru Nishita, Yasuhiro Minami, Zhongmin Lu, Katherina WalzMustafa Tekin

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    Abstract

    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 ethnicitymatched 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.

    Original languageEnglish
    Pages (from-to)5993-5998
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume113
    Issue number21
    DOIs
    Publication statusPublished - 24 May 2016

    Keywords

    • Deafness
    • Inner ear|innervation
    • Nf-κb
    • Whole-exome sequencing

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