The Role of Ankrd6 in Mammalian Inner Ear Development

Emory University, Atlanta GA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The organ of Corti, the sensory organ of the mammalian inner ear, contains mechanosensory hair cells that are uniformly oriented, such that the V-shaped stereocilia bundles at their lumenal surfaces point to the periphery of the sensory epithelium. This uniform orientation that is parallel to the plane of the sensory epithelium is called Planar Cell Polarity (PCP). The polar morphology of the stereocilia bundles is critical for maximal hearing sensitivity and the proper transduction of the mechanical sound stimulus. Mutations in genes that affect the polarity of the stereocilia lead to deafness. Studies in both invertebrate model systems, such as Drosophila, and vertebrate model systems have identified components of a conserved signaling pathway that regulates PCP. Moreover, recent studies have revealed that mammalian homologs of PCP components play an essential role in regulating PCP in the organ of Corti during inner ear development. However, the molecular mechanisms that establish and maintain this polarity are unclear. Preliminary data from our lab has identified a novel mammalian PCP candidate called Ankrd6. This application proposes three specific aims to examine the role of Ankrd6 in mammalian inner ear development and to test whether Ankrd6 regulates PCP in the organ of Corti. Aim 1 will characterize the spatial and temporal expression of Ankrd6 protein in the development of the mouse inner ear by immunohistochemistry. Aim 2 will characterize the loss of AnkrdG function on mouse inner ear development using targeted mouse knockout strategies. Aim 3 will characterize the molecular and genetic relationships between Ankrd6 and known mammalian PCP components. The research plan will exploit the conservation of the PCP pathway between invertebrates and vertebrates and employ experiments that will combine the strengths of two model systems, Drosophila and mouse. The long-term objective of this proposal is to elucidate the molecular mechanisms that regulate PCP in the organ of Corti in order to understand how genetic perturbations in factors that regulate this essential developmental process might lead to deafness. RELEVANCE. Hearing loss affects 4 in 1000 newborns. Genetic factors are believed to cause at least 50% of cases of congenital hearing loss. This research proposal will examine one of many genetic factors that may contribute to human deafness. [unreadable] [unreadable] [unreadable]