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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-B (04))
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Freeman, Nancy
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Emory University
Anatomy/Cell Biology
Schools of Medicine
United States
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Gao, Zhen; Kelly, Michael C; Yu, Dehong et al. (2016) Spatial and Age-Dependent Hair Cell Generation in the Postnatal Mammalian Utricle. Mol Neurobiol 53:1601-1612
Bhonker, Yoni; Abu-Rayyan, Amal; Ushakov, Kathy et al. (2016) The GPSM2/LGN GoLoco motifs are essential for hearing. Mamm Genome 27:29-46
Jones, Chonnettia; Qian, Dong; Kim, Sun Myoung et al. (2014) Ankrd6 is a mammalian functional homolog of Drosophila planar cell polarity gene diego and regulates coordinated cellular orientation in the mouse inner ear. Dev Biol 395:62-72
Yuan, Yongyi; Zhang, Jianguo; Chang, Qing et al. (2014) De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome. Cell Res 24:1370-3
Ren, Dong-Dong; Kelly, Michael; Kim, Sun Myoung et al. (2013) Testin interacts with vangl2 genetically to regulate inner ear sensory cell orientation and the normal development of the female reproductive tract in mice. Dev Dyn 242:1454-65
Chacon-Heszele, Maria F; Ren, Dongdong; Reynolds, Albert B et al. (2012) Regulation of cochlear convergent extension by the vertebrate planar cell polarity pathway is dependent on p120-catenin. Development 139:968-78
Kelly, Michael C; Chang, Qing; Pan, Alex et al. (2012) Atoh1 directs the formation of sensory mosaics and induces cell proliferation in the postnatal mammalian cochlea in vivo. J Neurosci 32:6699-710
Li, Shuangding; Esterberg, Robert; Lachance, Veronik et al. (2011) Rack1 is required for Vangl2 membrane localization and planar cell polarity signaling while attenuating canonical Wnt activity. Proc Natl Acad Sci U S A 108:2264-9
Vivancos, Valérie; Chen, Ping; Spassky, Nathalie et al. (2009) Wnt activity guides facial branchiomotor neuron migration, and involves the PCP pathway and JNK and ROCK kinases. Neural Dev 4:7
Kelly, Michael C; Chen, Ping (2009) Development of form and function in the mammalian cochlea. Curr Opin Neurobiol 19:395-401

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