Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer

Abstract

Cochlear hair cells form the sound-sensing apparatus of vertebrates and their loss or damage results in hearing impairment. Mammals cannot regenerate these cells, but previous work has shown that ectopic expression of the transcription factor Atonal homologue 1 (Atoh1) can induce cells that would not normally differentiate as cochlear hair cells to become hair cell-like. Now Gubbels et al. show that in utero gene transfer of Atoh1 into mouse cochleas generates ectopic hair cells in the cochlea. Importantly, these supernumerary hair cells are functionally competent and display neuronal connectivity. This is a major step towards experiments to test for the ability of gene therapies to ameliorate hearing loss in mouse models of human deafness. Sensory hair cells in the mammalian cochlea convert mechanical stimuli into electrical impulses that subserve audition1,2. Loss of hair cells and their innervating neurons is the most frequent cause of hearing impairment3. Atonal homologue 1 (encoded by Atoh1, also known as Math1) is a basic helix–loop–helix transcription factor required for hair-cell development4,5,6, and its misexpression in vitro7,8 and in vivo9,10 generates hair-cell-like cells. Atoh1-based gene therapy to ameliorate auditory10 and vestibular11 dysfunction has been proposed. However, the biophysical properties of putative hair cells induced by Atoh1 misexpression have not been characterized. Here we show that in utero gene transfer of Atoh1 produces functional supernumerary hair cells in the mouse cochlea. The induced hair cells display stereociliary bundles, attract neuronal processes and express the ribbon synapse marker carboxy-terminal binding protein 2 (refs 12,13). Moreover, the hair cells are capable of mechanoelectrical transduction1,2 and show basolateral conductances with age-appropriate specializations. Our results demonstrate that manipulation of cell fate by transcription factor misexpression produces functional sensory cells in the postnatal mammalian cochlea. We expect that our in utero gene transfer paradigm will enable the design and validation of gene therapies to ameliorate hearing loss in mouse models of human deafness14,15.