David P. Corey, Ph.D.
Professor of Neurobiology
Harvard Medical School/Massachusetts General Hospital
Department of Neurobiology

MRRC Project(s)

P01 HD24926-11
Molecular Basis of Inherited Deafness

The transcription factor of 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 necessary for development of hair cells, and consequently are candidate genes for inherited deafness.

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.

This 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 stably transfected osteosarcoma cells with Math1 under 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.

.

Publications

Liu XZ, Ouyang XM, Xia XJ, Zheng J, Pandya A, Li F, Du LL, Welch KO, Petit C, Smith RJ, Webb BT, Yan D, Arnos KS, Corey D, Dallos P, Nance WE, Chen ZY. Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss. Hum Mol Genet 2003;12(10):1155-62.

Meyers JR, MacDonald RB, Duggan A, Lenzi D, Standaert DG, Corwin JT, Corey DP. Lighting up the senses: FM1-43 loading of sensory cells through nonselective ion channels. J Neurosci 2003;23(10):4054-65.

Cheung EL, Corey DP. A gradient of single-channel conductance in the cochlea: tuning the cochlea's strings? Neuron 2003;40(5):875-6.

Corey DP. New TRP channels in hearing and mechanosensation. Neuron 2003;39(4):585-8.

Sukharev S, Corey DP. Mechanosensitive channels: multiplicity of families and gating paradigms. Sci STKE 2004;2004(219):re4.

Contact Information