PiN Faculty Member - David Corey, PhD

David Corey, PhD

Bertarelli Professor of Translational Medical Science
Investigator, Howard Hughes Medical Institute

Harvard Medical School
Department of Neurobiology
Goldenson Building, Room 443
220 Longwood Avenue
Boston, MA 2115
Tel: 617-432-2506
Fax: 617-432-2508
Email: dcorey@hms.harvard.edu
Visit my lab page here.



We are interested in the gating of mechanically sensitive ion channels, which open in response to force on the channel proteins. We study these channels primarily in vertebrate hair cells -- the receptor cells of the inner ear, which are sensitive to sounds or accelerations. Hair cells are epithelial cells, with a bundle of stereocilia rising from their apical surfaces. Mechanical deflection of the bundles changes the tension in fine "tip links" that stretch between the stereocilia; these filaments are thought to pull directly on the mechanically-gated transduction channels to regulate their opening.

Tip links are made of two unusual cadherins with long extracellular domains--cadherin 23 and protocadherin 15—whose N-termini join to complete the link. We are interested in the tip link’s biophysical properties and how the two cadherins join. We have determined the crystal structure of the cadherin-23 and protocadherin N-termini bound to each other, and have used steered molecular dynamics to determine their elastic properties and unbinding force. The crystal structures and molecular dynamics together have helped explain how deafness-producing mutations in the tip link disrupt its structure. These simulations are being confirmed in vitro by pulling apart the bound complexes with laser tweezers.

To identify new proteins of the mechanotransduction apparatus, we used fluorescence-activated cell sorting and RNA sequencing to determine the pattern of expression of all genes during development in hair cells. Selecting a few hundred genes expressed in hair cells but not surrounding cells, with expression increasing during differentiation, revealed many proteins known to be involved in hair cell function and known to be mutated in human inherited deafness. Additional proteins of this group may be similarly involved in hearing and deafness. A public database we created has been visited more than 700,000 times.

Identification of deafness genes also enables strategies to treat hereditary deafness.  We are using novel viral vectors to deliver genes to hair cells of mice bearing mutations in some of these genes, and have achieved partial restoration of hearing with gene therapy in a mouse model.

To understand the mechanics of hair cell transduction, we have characterized the movement of stereocilia bundle with high-resolution light microscopy and strobe illumination. Stereocilia do not bend, but pivot at their bases, and they remain touching within 10 nm even as they slide past one another by hundreds of nanometers. This “sliding adhesion” confers independent gating on transduction channels.  Candidate proteins that may mediate this adhesive mechanism are being tested with light and electron-microscopic imaging and in knockout mice.

The force-gated ion channel that is pulled open by tip-link tension is likely to be composed of two novel proteins, TMC1 and TMC2.  Other proteins, including protocadherin-15, TMHS and TMIE, are also required for mechanotransduction.  With a variety of physiological, biochemical, structural and and imaging methods, we are working toward a complete molecular description of the mechanotransduction complex.



Last Update: 8/18/2016



Publications

For a complete listing of publications click here.

 


 



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