Neuronal degeneration is a key determinant of impairment in many disorders of hearing and balance, and neuronal survival after hair cell loss is critical to the success of cochlear implants. Recent collaboration between our laboratories has suggested a role for the trophic factor neuregulin (NRG), and its receptors, the erbB family of tyrosine kinase receptors, in the normal development, proliferation and post-natal survival of hair cells and their sensory innervation. We developed a transgenic mouse in which normal NRG-erbB signaling is disrupted in the ear. Phenotypic analysis revealed a hearing disorder associated with post-natal, primary degeneration of cochlear nerve fibers (without hair cell loss) and a balance disorder associated with a reduction in the size of the vestibular sensory epithelium and the vestibular ganglion. Based on this transgenic mouse, the first cochlear model of primary post-natal neuronal degeneration, we hypothesize that NRG released by sensory neurons binds to erbB receptors on supporting cells in both cochlear and vestibular epithelia. In the cochlea, we hypothesize that NRG-erbB signaling causes support cells to release neurotrophins, e.g. NT-3, which, in turn, promote neuronal survival. In vestibular organs, we hypothesize that NRG-erbB signaling causes support-cell and hair-cell proliferation which indirectly promotes neuronal survival. This proposal combines expertise in cellular and molecular studies of neuronal development and survival with expertise in morpho-physiological characterization of ear disorders to test and refine these hypotheses concerning the role of NRG-erbB signaling in inner ear development and maintenance.
Specific aims use a combination of light and electron-microscopic morphometry, immunohistochemistry, in situ hybridization, quantitative RT-PCR and tissue culture to analyze the spatial and temporal expression patterns of key molecules in this signaling pathway (Aim 1); investigate, both in vivo and in vitro, the role of NRG-erbB signaling in the cochlea (Aim 2) and vestibular organs (Aim 3), and analyze the roles of NRG in the interactions between supporting cells and sensory neurons, using co-cultures. Completion of these aims will clarify important cellular and molecular mechanisms underlying the normal development and survival of hair cells and neurons in the inner ear. Results may help in devising treatments to prevent or retard neuronal degeneration and/or induce hair cell proliferation in sensorineural ear disorders.
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