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

Research output: Contribution to journalArticle

9 Scopus citations

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 (US)
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
StatePublished - May 24 2016

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Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Diaz-Horta, O., Abad, C., Sennaroglu, L., Ii, J. F., DeSmidt, A., Bademci, G., Tokgoz-Yilmaz, S., Duman, D., Cengiz, F. B., Grati, MH., Fitoz, S., Liu, X. Z., Farooq, A., Imtiaz, F., Currall, B. B., Morton, C. C., Nishita, M., Minami, Y., Lu, Z., ... Tekin, M. (2016). ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice. Proceedings of the National Academy of Sciences of the United States of America, 113(21), 5993-5998. https://doi.org/10.1073/pnas.1522512113