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

Proc Natl Acad Sci U S A. 2016 May 24;113(21):5993-8. doi: 10.1073/pnas.1522512113. Epub 2016 May 9.


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.

Keywords: NF-κB; deafness; inner ear; innervation; whole-exome sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Axons / pathology
  • Cell Line
  • Hair Cells, Auditory / metabolism*
  • Hair Cells, Auditory / pathology
  • Hearing Loss, Sensorineural / genetics
  • Hearing Loss, Sensorineural / metabolism*
  • Hearing Loss, Sensorineural / pathology
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Mutation*
  • Receptor Tyrosine Kinase-like Orphan Receptors / genetics
  • Receptor Tyrosine Kinase-like Orphan Receptors / metabolism*
  • Spiral Ganglion / metabolism*
  • Spiral Ganglion / pathology
  • Wnt-5a Protein / genetics
  • Wnt-5a Protein / metabolism


  • WNT5A protein, human
  • Wnt-5a Protein
  • Wnt5a protein, mouse
  • ROR1 protein, human
  • Receptor Tyrosine Kinase-like Orphan Receptors
  • Ror1 protein, mouse

Supplementary concepts

  • Deafness, Autosomal Recessive