Deafness is one of the most common hereditary diseases, affecting one out of 1000 children. Human geneticists have made remarkable progress in identifying genes responsible for deafness, yet in many cases, we do not clearly understand either the function these genes or the pathology caused by the mutations. Moreover, our understanding of the sense of hearing lags behind our knowledge of other senses such as vision, taste, and touch. The molecules that directly mediate mechanotransduction in hair cells have yet to be been identified. In order to gain insight into the molecular basis of mechanotransduction and the function of deafness genes, we will take advantage of both forward and reverse genetics in the model vertebrate organism, the zebrafish. We have identified a total of 24 genes required for larval auditory and vestibular function from large scale mutagenesis screens, and have cloned four zebrafish genes thus far. Orthologues of all four genes are responsible for deafness in either humans or mice, demonstrating the relevance of our screen and a high degree of conservation of gene function. We will continue our cloning efforts by candidate or positional cloning approaches. In addition, our reverse genetic studies have proven fruitful, identifying a potential candidate gene for the mechanotransduction channel, NompC. As further evidence for a direct role in transduction, we will localize the NompC channel in zebrafish hair cells. One particular challenge will be to characterize and pinpoint the nature of the defects in our mutants or morpholino-injected animals. We will therefore create a transgenic calcium indicator line that will enable us to determine whether transduction, synaptic transmission, or central processing of auditory signals is affected in our auditory/vestibular mutants. The data from these experiments will help to increase our understanding of the biology of deafness genes and may lead to potential therapies for deafness patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC006880-02
Application #
6917156
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (08))
Program Officer
Freeman, Nancy
Project Start
2004-07-06
Project End
2010-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$377,500
Indirect Cost
Name
Oregon Health and Science University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Sheets, Lavinia; He, Xinyi J; Olt, Jennifer et al. (2017) Enlargement of Ribbons in Zebrafish Hair Cells Increases Calcium Currents But Disrupts Afferent Spontaneous Activity and Timing of Stimulus Onset. J Neurosci 37:6299-6313
Nicolson, T (2015) Ribbon synapses in zebrafish hair cells. Hear Res 330:170-7
Sheets, Lavinia; Hagen, Matthew W; Nicolson, Teresa (2014) Characterization of Ribeye subunits in zebrafish hair cells reveals that exogenous Ribeye B-domain and CtBP1 localize to the basal ends of synaptic ribbons. PLoS One 9:e107256
Barr-Gillespie, Peter G; Nicolson, Teresa (2013) Who needs tip links? Backwards transduction by hair cells. J Gen Physiol 142:481-6
Clemens Grisham, Rachel; Kindt, Katie; Finger-Baier, Karin et al. (2013) Mutations in ap1b1 cause mistargeting of the Na(+)/K(+)-ATPase pump in sensory hair cells. PLoS One 8:e60866
Kindt, Katie S; Finch, Gabriel; Nicolson, Teresa (2012) Kinocilia mediate mechanosensitivity in developing zebrafish hair cells. Dev Cell 23:329-41
Einhorn, Zev; Trapani, Josef G; Liu, Qianyong et al. (2012) Rabconnectin3? promotes stable activity of the H+ pump on synaptic vesicles in hair cells. J Neurosci 32:11144-56
Sheets, Lavinia; Kindt, Katie S; Nicolson, Teresa (2012) Presynaptic CaV1.3 channels regulate synaptic ribbon size and are required for synaptic maintenance in sensory hair cells. J Neurosci 32:17273-86
Mo, Weike; Nicolson, Teresa (2011) Both pre- and postsynaptic activity of Nsf prevents degeneration of hair-cell synapses. PLoS One 6:e27146
Sheets, Lavinia; Trapani, Josef G; Mo, Weike et al. (2011) Ribeye is required for presynaptic Ca(V)1.3a channel localization and afferent innervation of sensory hair cells. Development 138:1309-19

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