Mutations in the transmembrane cochlear expressed gene 1 (TMC1) underlies dominant progressive hearing loss (DFNA36) and recessive nonsyndromic sensorineural hearing loss deafness (DFNB7/B11) (Kurima et al., 2002). Similarly, semidominant and recessive alleles of Tmc1 cause hearing loss in Beethoven (Bth) and Deafness (dn) mutant mice (Vreugde et al.,2002; Kurima et al., 2002). Tmc1 is a member of the Tmc gene family that includes seven other paralogs in mammals (Keresztes et al., 2003). Tmc1 and Tmc2 are expressed in hair cells of the inner ear. We have recently demonstrated that mice that lack Tmc1 and Tmc2 are deaf and suffer profound vestibular dysfunction. Interestingly, analysis of Tmc1 and Tmc2 mRNA expression during organ of Corti development revealed a tonotopic expression pattern and a developmental switch from Tmc2 to Tmc1 (Kawashima, G?l?oc et al. 2011). The rise of Tmc2 mRNA expression coincided with the developmental acquisition of hair cell transduction. Analysis of transduction currents in cochlear outer hair cells of mice lacking Tmc1 or Tmc2 revealed nearly normal responses during the first postnatal week. On the other hand, hair cells from double knockout mice that lacked Tmc1 and Tmc2 did not respond to mechanical stimulation at any time point during development or in any region along the organ of Corti despite the presence of normal hair bundle morphology. Based on these observations we hypothesize that Tmc1 and Tmc2 have redundant functions and that expression of either Tmc1 or Tmc2 is required for hair cell mechanotransduction. Since Tmc2 expression is transient during the first postnatal week, the developmental switch to Tmc1 at the end of the first postnatal week could explain the deafness phenotype associated with mutations in Tmc1 in mice and humans. To explore the temporal constraints of Tmc1 and Tmc2 expression, the developmental switch in expression and their functional redundancy, we will generate several novel mouse models with conditional deletion, conditional expression and inducible expression of Tmc1 and Tmc2 and assay for changes in the properties of mechanotranduction and auditory function.

Public Health Relevance

For this project we will investigate two genes, Tmc1 and Tmc2, which are required for normal sensory cell function in the inner ear. Although the precise role of Tmc1 and Tmc2 is unknown, it is clear they perform similar functions: if either gene is turned on, the sensory hair cells function normally. To better understand the function of these genes we will engineer mice that allow us to turn Tmc1 and Tmc2 on or off at any time throughout the life of these mice.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC008853-10
Application #
9319225
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Freeman, Nancy
Project Start
2007-07-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2019-07-31
Support Year
10
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Asai, Yukako; Pan, Bifeng; Nist-Lund, Carl et al. (2018) Transgenic Tmc2 expression preserves inner ear hair cells and vestibular function in mice lacking Tmc1. Sci Rep 8:12124
Avenarius, Matthew R; Jung, Jae-Yun; Askew, Charles et al. (2018) Grxcr2 is required for stereocilia morphogenesis in the cochlea. PLoS One 13:e0201713
Nakanishi, Hiroshi; Kurima, Kiyoto; Pan, Bifeng et al. (2018) Tmc2 expression partially restores auditory function in a mouse model of DFNB7/B11 deafness caused by loss of Tmc1 function. Sci Rep 8:12125
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Pan, Bifeng; Géléoc, Gwenaelle S; Asai, Yukako et al. (2013) TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron 79:504-15
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