Functional characterization of Netrin-1 in the spiral ganglion

Harvard Medical School, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): Spiral ganglion neurons (SGNs) serve as the sole connection between the ear and the brain by faithfully transmitting all sound information from mechanosensory hair cells to the auditory brainstem. Despite the importance of SGNs, little is known about the molecular mechanisms that regulate their development, in particular their migration, proliferation, and survival. These neurons delaminate from the otic vesicle, and upon their terminal mitoses, project neurites to the presumptive sensory epithelium. This development occurs in a highly complex environment. When SGNs first delaminate, they form a close association with vestibular and geniculate neurons; the ganglia gradually separate as they mature. SGN neurites also encounter mesenchymal cells and neural crest-derived glial precursors as they cross the cochlear duct. The resulting cell- cell interactions are critical to te generation of stereotyped, radial bundles of SGN neurites. Netrin-1 (Ntn1), an axon guidance cue, is expressed in the cochlea, but despite promoting SGN outgrowth in vitro, its function in the spiral ganglion remains unknown. No defects in SGN development have been reported in Ntn1 hypomorphs, the only existing Ntn1 mutant. To identify novel functions of Ntn1, we generated the first null allele of Ntn1 and discovered that Ntn1 mutant cochleae contain many ectopic neurons. Importantly, though Ntn1 is best known as an axon guidance cue, it has been shown to regulate a plethora of other cellular processes, including survival and adhesion. This finding suggests that Ntn1 either primarily regulates the proliferation or survival of SGNs or prevents the migration of ectopic neurons into the spiral ganglion during embryonic development. To test these hypotheses, I will use a combination of mouse genetics, molecular biology, imaging, and detailed phenotypic analysis. First, I will identify the cells that secrete Nn1 and fully characterize the neuronal phenotype by identifying what the ectopic neurons are and where they project. Second, I will identify the cells that can respond to Ntn1 and investigate whether defects in migration, proliferation, or survival-which are not mutually exclusive-can give rise to the ectopic neurons observed. Taken together, these two aims will simultaneously further our knowledge of spiral ganglion development and identify novel functions for Ntn1. Further, results from this proposal could yield potential therapeutic targets for hearing loss, as SGNs are frequently damaged following cochlear damage or exposure to loud sounds.