Auditory/vestibular hair cells are excited by sound or head movements. Excitation occurs when hair bundles are deflected along the excitatory axis, placing tension on tips links that interconnect stereocilia. Tension is thought to mechanically gate cation- selective channels at the tips of stereocilia. To date, collective evidence indicates that two novel cadherins, Cadherin 23 (Cdh23) and Protocadherin 15 (Pcdh15), form the extracellular tip links between stereocilia and are thus critical members of the transduction machinery. Other members of the transduction complex are thought to include Harmonin, Myosin 1c, Myosin 15 and Whirlin. Although a number of candidates for the mechanotransduction channel have been put forth, the identity of the transduction channel in hair cells remains elusive. We hope to identify the components involved in hair cell function, particularly those required for mechanosensory transduction and synaptic transmission using forward genetics. By screening over 7000 genomes (Tuebingen Screens I & II), we have identified a total of 24 genes that are required for balance and hearing in zebrafish. These circler mutants are analogous to the mouse shaker-waltzer mutants and may help us to identify genes which are required for the function of mechanosensory organs such as the inner ear and lateral line system. We are also using reverse genetics to identify components of the hair cell transduction apparatus and to generate animal models for human hereditary deafness.