Single cell RNA-seq of cochlear tissues from Tmie+/- and Tmie-/- mice, a model for recessive non-syndromic deafness model 6.

Deafness is the most common form of sensory impairment in humans and frequently caused by defects in hair cells of the inner ear. Here we demonstrate that in a mouse model for recessive non-syndromic deafness (DFNB6), inactivation of Tmie in hair cells disrupts gene expression in the neurons that innervate them. This includes genes regulating axonal pathfinding and synaptogenesis, two processes that are disrupted in the inner ear of the mutant mice. Similar defects are observed in mouse models for deafness caused by mutations in other genes with primary functions in hair cells. Gene therapy targeting hair cells restores hearing and inner ear circuitry in DFNB6 model mice. We conclude that hair cell function is crucial for the establishment of peripheral auditory circuitry. Treatment modalities for deafness thus need to consider restoration of the function of both hair cells and neurons, even when the primary defect occurs in hair cells. Cochlear tissues (including the spiral ganglion, spiral limbus, inner sulcus, organ of Corti, and outer sulcus) from postnatal day 21 aged (P21) Tmie-/- (KO) mice and heterozygous Tmie+/- (HET) littermate controls were isolated and analyzed by scRNA-seq.