The organ of Corti consists of 4 parallel rows of sensory hair cells along the length of the cochlear duct. On the apical surface of each hair cell, F actin-filled stereociliary bundles form a "V"-shaped structure. Invariably, the vertices of "V"-shaped stereocilia of all the hair cells point to the periphery of the cochlea, displaying a polarity that is parallel to the sensory epithelium and known as planar cell polarity (PCP). The precise arrangement and polarity of hair cells is essential for auditory transduction. Defects in the patterning of hair cells and stereocilia are responsible for many forms of deafness. During development, the polarity of stereocilia in a hair cell is preceded by the polarity of a tubulin- based primary cilium, known as the kinocilium. In this proposal, we will test our hypothesis that genes required for the formation of kinocilia are involved in PCP regulation at multiple steps for normal morphogenesis of the organ of Corti. We will achieve four specific aims. We will characterize ciliogenesis in the developing inner ear to establish developmental stages and molecular markers for functional analysis of ciliary genes (SA1). We will test whether a ciliary gene Polaris or intraflagellar transport 88 (IFT88) is required for initiating PCP signaling in the inner ear (SA2). We will also test whether ciliary genes are required for polarization of the basal body, which tethers the ciliary axoneme to the cell and organizes cytoskeleton, and whether ciliary proteins interact with the Usher complex to build intrinsically polarized stereociliary bundles (SA3). Finally, we will determine whether ciliary genes are required for PCP maintenance and have cilia-independent roles (SA4). Cellular and tissue polarity is a fundamental issue in biology. The development and function of a multicellular organism depends on many types of cellular polarities. The organ of Corti represents the most distinctive vertebrate example of PCP and emerges as a model system for cellular polarity studies. In addition, ciliary genes have been studied extensively in biomedical field due to their important contributions to other aspects of human development and diseases. Our proposed study of ciliary genes and PCP signaling in the organ of Corti may reveal new roles for ciliary genes, uncover mechanisms underlying PCP regulation of cellular polarity, and promises a unique opportunity to address fundamental biological issues. This study may also lead to a better understanding of the molecular and cellular basis for many forms of human deafness and provide useful tools to explore regeneration of the inner ear sensory organs.
This project studies how the mammalian auditory sensory organ achieves its unique structure that is essential for sound transduction. The proposed studies may lead to a better understanding of the molecular and cellular basis for human deafness and provide useful tools to rejuvenate the developmental program for regeneration.
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