INNER EAR-DERIVED FACTORS IN AUDITORY DEVELOPMENT

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During auditory development, sensory nerve fibers from the statoacoustic ganglion (SAG) extend toward the otocyst to contact their target hair cells. The developmental mechanisms regulating these events are largely unknown. Experiments demonstrating that the otocyst releases a diffusible factor that promotes SAG outgrowth suggest the otocyst plays a crucial role in the initiation and extension of SAG nerve fibers. Recent experiments further indicate that other growth factors are released at even later stages of development, suggesting a role for growth factors over a broad period of auditory development. The goal of this proposal is to define the role of neurotrophic factors released by the inner ear in auditory development. The experiments utilize our ability to culture growth factors released by the inner ear to study how they influence cultures of chick SAG neurons. Specifically, the proposed experiments will first reveal the types of growth factors released by inner ear tissue, the period of their release, and the temporal dependence of different stage (E4-E15) SAG neurons on these factors. SAG will be dissociated to obtain neuron-enriched cultures in which the effects of factors will be studied directly on individual neurons. Auditory and vestibular portions of SAG will be cultured separately for embryonic stages E6 and older, when these portions become distinct. Second, the identity of the inner ear-derived factors will be studied using biochemical techniques to provide further information on developmental changes in inner ear-derived growth factors. We will evaluate the biochemical properties of proteins released by otocysts (E4-E6) and later stage inner ears (E9-E15). Third, additional neurite-promoting interactions between SAG glial cells (Schwann and satellite cells) and SAG neurons will be studied. Our long term goals are to reveal the importance and identity of growth factors released by the inner ear in regulating the development of auditory and vestibular neurons. By using the avian model, the proposed experiments may also reveal the conditions necessary for promoting connections between regenerated hair cells and mature auditory nerve fibers. The experiments will not only define the mechanisms controlling auditory development but they may also suggest novel strategies for the treatment of hearing impairment by providing a means to stimulate the outgrowth of damaged auditory neurons.