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.
Authors: Making the paper: John Brigande
Tuning in to how genes control hearing development.
News and Views: Hearing: Route to authentic hair cells
Existing therapies for hearing defects are generally ineffective in severe
forms of deafness. A technical feat that generates sound-sensing hair cells in
the inner ear of mice might have long-term potential.
Nature 455, 537-541 (25 September 2008) | doi:10.1038/nature07265
Functional auditory hair cells produced in the mammalian cochlea by in utero
Samuel P. Gubbels1,4,5, David W. Woessner1,4,5, John C. Mitchell2, Anthony J.
Ricci3 & John V. Brigande1
1. Department of Otolaryngology, Oregon Hearing Research Center, and,
2. Department of Restorative Dentistry, Division of Biomaterials and
Biomechanics, School of Dentistry, Oregon Health & Science University, 3181 SW
Sam Jackson Park Road, Portland, Oregon 97239, USA
3. Department of Otolaryngology-Head and Neck Surgery, Stanford University
School of Medicine, 801 Welch Road, Stanford, California 94305, USA
4. These authors contributed equally to this work.
5. Present addresses: Department of Surgery, Division of Otolaryngology,
University of Wisconsin – Madison, K4/719 CSC, 600 Highland Avenue, Madison,
Wisconsin 53792, USA (S.P.G.); Department of Pharmacology and Toxicology,
University of Utah, College of Pharmacy, 30 South 2000 East, Room 201, Salt
Lake City, Utah 84112, USA (D.W.W.).
Correspondence to: John V. Brigande1 Correspondence and requests for materials
should be addressed to J.V.B. (Email:
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 vitro 7, 8 and in vivo 9, 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 a!
re 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.
XIAO, Jianqiang, Ph.D.
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