LS-10-P-6013 The Role of Klc2 in Hearing and Deafness

Our hearing organ, the organ of Corti (OC), is exquisitely sensitive- able to detect one hundred trillion units of sound intensity, across a range of frequencies that spans several orders of magnitude. In normal hearing, sound, a mechanical stimulus is converted to an electrical signal that triggers neural activation. This is accomplished by specialized sensory hair cells in a process called mechanotransduction, which relies on a combination of extracellular protein filaments, transmembrane complexes including ion channels, actin-based stereocilia and actin-associated intracellular motor proteins. The sophisticated micromechanics underlying our ability to hear would not be possible without the unique morphologies and remarkable patterning of hair cells and non-sensory support cells of the OC (Figure 1). Each cell type within the OC has a characteristic cytoskeletal architecture that is defined by different arrangements and dynamics of actin filaments and microtubules. Accordingly, mutations in actin as well as a number of actin regulatory proteins and microtubule-associated proteins have been associated with hearing disorders. We have recently identified, from the Wellcome Trust Sanger Institute Mouse Genetics Project screen for hearing defects, that the mutation of the cytoskeleton-associated Klc2 gene, which encodes kinesin light chain 2 (KLC2), causes a progressive hearing loss in mice. Kinesins are a family of molecular motor proteins that move along polarized microtubules to transport macromolecular cargo using energy obtained from ATP hydrolysis, and kinesin light chains are involved in cargo-binding. We are currently using a combination of microscopy techniques to characterize the Klc2 mutant mouse, to elucidate the role of Klc2 in progressive hearing loss. The localization of Klc2 in the inner ear is being investigated using immunofluorescence together with confocal fluorescence microscopy; the apical morphology of the OC in the Klc2-/- mouse is being assessed using scanning electron microscopy; and the ultrastructure of hair cells and synapses interrogated using transmission electron microscopy. Together, these data will provide novel insights into the role of Klc2 in progressive hearing loss, but importantly also add to existing knowledge on the molecular bases of normal hearing and deafness.