The identification of gene mutations associated with hearing loss in humans and animal models has contributed greatly to our understanding of cell type specific functions in the inner ear. Despite this progress, the cause of inherited forms of hearing loss still remains unknown in many cases, suggesting that the discovery of new genes associated with sensorineural hearing loss (SNHL) is far from saturated. To fill this gap, we performed a screen for novel regulators of cochlear development and identified several genes that are predicted to play important roles in cochlear function. We generated a mouse knockout for one of these genes, Growth arrest specific 2 (Gas2), encoding a putative cytoskeletal regulatory protein. Gas2 knockout mice display severe hearing loss with no alterations in inner ear development at embryonic stages. Instead, we propose that the cause of hearing loss is due to a progressive destabilization of the microtubule cytoskeleton in pillar and Deiters? cells, two specialized support cells in the organ of Corti that are thought to provide tensile strength and a structural framework for transferring mechanical forces during sound-evoked vibrations. The experiments in this grant proposal are designed to transform our understanding of the role that support cells play in cochlear function. Firstly, we will test the hypothesis that Gas2 dependent stabilization of microtubule bundles in pillar and Deiters? cells is required for hearing. Secondly, we will determine the influence of Gas2 and a-tubulin detyrosination on cell surface mechanical properties and microtubule dynamics. Finally, we will pursue the exciting possibility that viral delivery of Gas2 to support cells might prevent hearing loss when administered prior to the onset of symptoms in neonatal Gas2 knockout mice, and even more provocatively, might repair the cytoskeletal defects and restore hearing when administered to adults. Taken together, these experiments will clarify the proposed role of Gas2 as a microtubule and actin cross-linking protein that is required to stabilize microtubule bundles in cochlear support cells and that this activity is necessary for auditory function.

Public Health Relevance

The identification of gene mutations associated with hearing loss in humans and animal models has contributed greatly to our understanding of cell type specific functions in the inner ear. Experiments in this grant proposal are strongly motivated by the premise that a detailed elaboration of the molecular and cellular mechanisms of cochlear development and function will not only provide better insight into the workings of this complex sensory organ, but may also profoundly change the way inner ear disorders, including hearing loss, are treated in the future.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
Project #
Application #
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
Rohacek, Alex M; Bebee, Thomas W; Tilton, Richard K et al. (2017) ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development. Dev Cell 43:318-331.e5
Brown, Alexander S; Rakowiecki, Staci M; Li, James Y H et al. (2015) The cochlear sensory epithelium derives from Wnt responsive cells in the dorsomedial otic cup. Dev Biol 399:177-87
Rakowiecki, Staci; Epstein, Douglas J (2013) Divergent roles for Wnt/?-catenin signaling in epithelial maintenance and breakdown during semicircular canal formation. Development 140:1730-9
Brown, Alexander S; Epstein, Douglas J (2011) Otic ablation of smoothened reveals direct and indirect requirements for Hedgehog signaling in inner ear development. Development 138:3967-76
Pachikara, Abraham; Dolson, Diane K; Martinu, Lenka et al. (2007) Activation of Class I transcription factors by low level Sonic hedgehog signaling is mediated by Gli2-dependent and independent mechanisms. Dev Biol 305:52-62
Cohen, Ethan David; Wang, Zhishan; Lepore, John J et al. (2007) Wnt/beta-catenin signaling promotes expansion of Isl-1-positive cardiac progenitor cells through regulation of FGF signaling. J Clin Invest 117:1794-804
Bok, Jinwoong; Dolson, Diane K; Hill, Patrick et al. (2007) Opposing gradients of Gli repressor and activators mediate Shh signaling along the dorsoventral axis of the inner ear. Development 134:1713-22
Riccomagno, Martin M; Takada, Shinji; Epstein, Douglas J (2005) Wnt-dependent regulation of inner ear morphogenesis is balanced by the opposing and supporting roles of Shh. Genes Dev 19:1612-23