The transcription factor Math1 is necessary for the development and survival of hair cells in the inner ear. At least some of the genes that are activated by Math1 in hair cells are therefore necessary for development of hair cells, and consequently are candidate genes for inherited deafness. Although over 70 gene loci for human nonsyndromic deafness have been found, the genes for only 14 have been identified. This study will help identify others. Moreover, adjacent supporting cells in cochlea can differentiate into hair cells if transfected with Math1, although other cell types cannot. Thus identification of the genes activated by Math1, and of the hair-cell-specific binding partners of Math1, may reveal genes that could promote regeneration of hair cells. Age-related hearing loss, which affects tens of millions of Americans, often results from the death of hair cells and could be ameliorated by the regeneration of hair cells from supporting cells. The proposed project seeks to identify genes activated by Math1 in hair cells, using GeneChips to screen RNAs derived from several different approaches. It will first identify class I basic helix-loop-helix transcription factors that form heteromultimers with Math1 in hair cells, using GeneChip data from normal hair cells, RT-PCR, and co-immunoprecipitation in transfected cells. It will then use GeneChips to identify candidate target genes of Math1, in a cochlea cell line transfected with Math1, in stablytransfected osteosarcoma cells with Math1 under a tetracycline repressor, and in mice lacking Math1. In a third aim, it will test these candidates by determining whether they are expressed in hair cells at an appropriate developmental phase, and whether Math1 can activate a reporter gene under the control of the candidate-gene promoter. Finally, the chromosomal locations of confirmed candidates will be compared to deafness loci in human and mouse, to produce additional candidates for deafness genes. Since Math1 is necessary and (in some cell types) sufficient for the generation of hair cells, this study should teach us much about how a hair cell becomes a hair cell. ? ?

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
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Special Emphasis Panel (ZRG1-IFCN-6 (01))
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Watson, Bracie
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Harvard University
Schools of Medicine
United States
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Krey, Jocelyn F; Scheffer, Deborah I; Choi, Dongseok et al. (2018) Mass spectrometry quantitation of proteins from small pools of developing auditory and vestibular cells. Sci Data 5:180128
Gy├Ârgy, Bence; Sage, Cyrille; Indzhykulian, Artur A et al. (2017) Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV. Mol Ther 25:379-391
Powers, Robert E; Gaudet, Rachelle; Sotomayor, Marcos (2017) A Partial Calcium-Free Linker Confers Flexibility to Inner-Ear Protocadherin-15. Structure 25:482-495
Avenarius, Matthew R; Krey, Jocelyn F; Dumont, Rachel A et al. (2017) Heterodimeric capping protein is required for stereocilia length and width regulation. J Cell Biol 216:3861-3881
Zhao, Hongyu; Shen, Ao; Xiang, Yang K et al. (2016) Three Recombinant Engineered Antibodies against Recombinant Tags with High Affinity and Specificity. PLoS One 11:e0150125
Vogl, Christian; Panou, Iliana; Yamanbaeva, Gulnara et al. (2016) Tryptophan-rich basic protein (WRB) mediates insertion of the tail-anchored protein otoferlin and is required for hair cell exocytosis and hearing. EMBO J 35:2536-2552
Lin, Shuh-Yow; Vollrath, Melissa A; Mangosing, Sara et al. (2016) The zebrafish pinball wizard gene encodes WRB, a tail-anchored-protein receptor essential for inner-ear hair cells and retinal photoreceptors. J Physiol 594:895-914
Rivera-Monroy, Jhon; Musiol, Lena; Unthan-Fechner, Kirsten et al. (2016) Mice lacking WRB reveal differential biogenesis requirements of tail-anchored proteins in vivo. Sci Rep 6:39464
Kwan, Kelvin Y; Shen, Jun; Corey, David P (2015) C-MYC transcriptionally amplifies SOX2 target genes to regulate self-renewal in multipotent otic progenitor cells. Stem Cell Reports 4:47-60
Vuckovic, Dragana; Dawson, Sally; Scheffer, Deborah I et al. (2015) Genome-wide association analysis on normal hearing function identifies PCDH20 and SLC28A3 as candidates for hearing function and loss. Hum Mol Genet 24:5655-64

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