Genetic Dissection of Auditory Circuit Assembly

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6. Project Summary/Abstract Hearing begins with the detection of sound by hair cells in the cochlea of the inner ear. Spiral ganglion neurons provide the sole conduit for auditory information from hair cells to the central nervous system. Loss of auditory neurons occurs in response to injury, tumors, or hair cell degeneration, which are all common causes of human congenital and age-related deafness. The most effective treatment for deafness is the cochlear implant, which works by directly stimulating spiral ganglion neurons, emphasizing the need to maintain properly wired connections between the ear and the brain. Understanding how auditory neurons are patterned and wired during development will provide an important foundation for the design of therapies to protect inner ear neurons from degeneration and for the development of stem-cell based methods for neuronal replacement. A central question in auditory neuroscience is how spiral ganglion neurons acquire properties that are specific for the perception of sound. Spiral ganglion neurons originate together with vestibular ganglion neurons within a common neurogenic region of the otic vesicle. Precisely wired auditory circuits form through a series of events, including the extension of processes towards hair cells, bifurcation of projections in the cochlear nucleus, and the formation of specialized synapses with target neurons in the brainstem. Many of these events are highlighted by comparison with vestibular ganglion neurons, which underlie the perception of balance and therefore make a distinct series of wiring decisions within the same local environment. The transcription factor GATA3 is produced in auditory but not vestibular neurons. Based on its activity as a master regulator in other developing systems, GATA3 is hypothesized to coordinate auditory-specific programs of development in spiral ganglion neurons. There are three goals: 1) to compare gene expression profiles in highly purified spiral and vestibular ganglion neurons in order to define the auditory-specific programs of circuit assembly underlying specific wiring events 2) to understand how GATA3 exerts distinct effects on early and late wiring events by generating and analyzing conditional knock-out mice; and 3) to identify auditory-specific genes that act downstream of GATA3 to regulate multiple stages of circuit formation. Results from these experiments will provide key insights into the unique cellular and molecular properties of auditory neurons, and may shed light on the etiology of deafness associated with hypoparathyroidism, sensorineural deafness, and renal anomalies (HDR), which is caused by mutations in GATA3.