The long-term goal of my laboratory is to elucidate the mechanisms that control mechanoelectrical transduction (MET) in hair cells, and the defects in this process that cause deafness. We propose here to study the function of the cell adhesion molecules cadherin 23 (CDH23) and protocadherin 15 (PCDH15) in hair cell function and disease. Previous studies have shown that CDH23 and PCDH15 are required for hair bundle development. Recent findings show that CDH23 and PCDH15 are components of extracellular filaments that connect stereocilia not only in developing but also in functionally mature hair cells. Based on these findings and new preliminary data, we hypothesis that CDH23 and PCDH15 are components of larger transmembrane signaling complexes in hair cells that control not only hair bundle morphogenesis but also MET. We predict that alternative splicing regulates the assembly and function of these protein complexes. To test our hypothesis, we will: (i) Determine the function of CDH23 for MET using genetically modified mice that were designed to circumvent developmental hair cell defects that are associated with CDH23 null alleles;(ii) define the function of PCDH15 splice variants for hair cell development and MET;(iii) isolate by yeast-two-hybrid assays novel components of CDH23 and PCDH15 dependent adhesion complexes in hair cells;(iv) analyze mouse lines with mutations in CDH23 that mimic mutations in patients suffering from Usher Syndrome 1D and autosomal recessive deafness DFNB12. We anticipate that mutations that are associated with different disease phenotypes affects distinct aspects of CDH23 function in hair cells. Deafness is a major health problem. 1 in 1000 children is born with hearing impairment and large parts of the aging population are afflicted by age-related hearing loss. In recent years, dramatic progress has been made in identifying gene mutations that cause deafness, but we know comparatively little about the mechanisms by which mutations in the affected genes cause deafness. We propose here to study the function of two genes that have been linked to deafness, Cdh23 and Pcdh15, in hair cells. Based on published and preliminary data, we anticipate that the two genes are required both for the development and function of mechanosensory hair cells, and that different mutations in the two genes that cause syndromic and non-syndromic forms of deafness affect distinct aspects of gene function in hair cells.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Auditory System Study Section (AUD)
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Watson, Bracie
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Scripps Research Institute
La Jolla
United States
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Zhao, Bo; Wu, Zizhen; Grillet, Nicolas et al. (2014) TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells. Neuron 84:954-67
Xiong, Wei; Wagner, Thomas; Yan, Linxuan et al. (2014) Using injectoporation to deliver genes to mechanosensory hair cells. Nat Protoc 9:2438-49
Kazmierczak, Piotr; Muller, Ulrich (2012) Sensing sound: molecules that orchestrate mechanotransduction by hair cells. Trends Neurosci 35:220-9
Webb, Stuart W; Grillet, Nicolas; Andrade, Leonardo R et al. (2011) Regulation of PCDH15 function in mechanosensory hair cells by alternative splicing of the cytoplasmic domain. Development 138:1607-17
Lelli, Andrea; Kazmierczak, Piotr; Kawashima, Yoshiyuki et al. (2010) Development and regeneration of sensory transduction in auditory hair cells requires functional interaction between cadherin-23 and protocadherin-15. J Neurosci 30:11259-69
Schwander, Martin; Kachar, Bechara; Müller, Ulrich (2010) Review series: The cell biology of hearing. J Cell Biol 190:9-20
Elledge, Heather M; Kazmierczak, Piotr; Clark, Peter et al. (2010) Structure of the N terminus of cadherin 23 reveals a new adhesion mechanism for a subset of cadherin superfamily members. Proc Natl Acad Sci U S A 107:10708-12
Gillespie, Peter G; Muller, Ulrich (2009) Mechanotransduction by hair cells: models, molecules, and mechanisms. Cell 139:33-44
Grillet, Nicolas; Xiong, Wei; Reynolds, Anna et al. (2009) Harmonin mutations cause mechanotransduction defects in cochlear hair cells. Neuron 62:375-87
Schwander, Martin; Lopes, Vanda; Sczaniecka, Anna et al. (2009) A novel allele of myosin VIIa reveals a critical function for the C-terminal FERM domain for melanosome transport in retinal pigment epithelial cells. J Neurosci 29:15810-8

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