Journal Article

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

Woessner, David W., Mitchell, John C., Ricci, Anthony J., Brigande, John V., Gubbels, Samuel P.

2008

Overview

Hair-cell triggers 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 i n 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 audition 1 , 2 . Loss of hair cells and their innervating neurons is the most frequent cause of hearing impairment 3 . Atonal homologue 1 (encoded by Atoh1 , also known as Math1 ) is a basic helix–loop–helix transcription factor required for hair-cell development 4 , 5 , 6 , and its misexpression in vitro 7 , 8 and in vivo 9 , 10 generates hair-cell-like cells. Atoh1 -based gene therapy to ameliorate auditory 10 and vestibular 11 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 transduction 1 , 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 deafness 14 , 15 .

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Animals / Basic Helix-Loop-Helix Transcription Factors - genetics / Basic Helix-Loop-Helix Transcription Factors - metabolism / Biological and medical sciences / Cell cycle / Cochlea / Cochlea - cytology / Cochlea - embryology / Cochlea - growth & development / Cochlea - innervation / Cochlea - metabolism / Deafness - genetics / Deafness - therapy / Disease Models, Animal / Dyneins - metabolism / Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology / Ears & hearing / Electric Conductivity / Embryology: invertebrates and vertebrates. Teratology / Female / Fundamental and applied biological sciences. Psychology / Gene therapy / Genetic aspects / Genetic Therapy / Genetic transformation / Hair / Hair Cells, Auditory - cytology / Hair Cells, Auditory - physiology / Hearing loss / Humanities and Social Sciences / Humans / letter / Mammals / Mechanotransduction, Cellular / Medical sciences / Mice / multidisciplinary / Myosin VIIa / Myosins - metabolism / Non tumoral diseases / Organogenesis. Fetal development / Organogenesis. Physiological fonctions / Otorhinolaryngology. Stomatology / Pregnancy / Proteins / Scanning electron microscopy / Science / Science (multidisciplinary) / Synapses - metabolism / Transfection / Uterus