A large number of genes have recently been identified that are implicated in vestibular disorders and in development of inner ear hair cells. Mouse models in which these genes can be inactivated in a hair cell-specific, temporally controlled manner are crucial to in vivo functional studies of these genes. However, to date there has been no effective method of conditional gene targeting in hair cells in vivo. This proposal seeks to overcome the limitations of traditional transgenic methods by expressing the bacterial recombinase Cre specifically and inducibly in vestibular and cochlear hair cells in transgenic mice. Preliminary studies have succeeded in creating and characterizing transgenic mice in which the reporter gene green fluorescent protein (GFP) is expressed specifically and abundantly in developing and adult hair cells of the vestibular and cochlear sensory epithelia. This success was achieved through the novel approach of modifying a bacterial artificial chromosome (BAC) that contains the alpha-9 AChR gene, which is important to efferent innervation and specific to vestibular and cochlear hair cells.
The specific aims of this proposal are to: 1. Create mice in which Cre is expressed specifically in vestibular and cochlear hair cells. 2. Create mice in which Cre is activated specifically in vestibular and cochlear hair cells only when an exogenous ligand is delivered. The creation and characterization of these Cre-hair cell mice will greatly facilitate studies of gene function in sensory-motor systems responsive to gravity. Ultimately, such studies will also contribute to the understanding, prevention, and treatment of vestibular diseases in humans. All mice made in FVB/N strain will be available to the academic community.
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