The overall goal of this proposal is to define the genetic and molecular pathways regulating hair cell regeneration. Forward genetic screens provide an unbiased approach to identifying genes required for normal regeneration. The zebrafish is uniquely suited for a screen to identify mutants with abnormal hair cell regeneration hair cells in the lateral line are on the outside of the body and readily accessible for visualization and manipulation. Genes identified during this screen for abnormal regeneration will be mapped and characterized and the function of these genes will provide insights as to the cellular and molecular biology regulating regeneration in the zebrafish lateral line. Understanding regeneration of these specialized mechanosensory cells may provide insights applicable to human heath, particularly age related hearing loss and balance disorders. Replacement of hair cells is common in fish and other non-mammalian vertebrates but does not occur in humans. Understanding the genetic and molecular components underlying hair cell regeneration in zebrafish may contribute to treating or even preventing hair cell loss in humans. This proposal describes the characterization of moby-1, a regeneration mutant identified in preliminary screening and presents three research aims: characterization of 3 additional mutants, further analysis of mby-1 to determine whether decreased regeneration is the result of decreased proliferation or precocious termination and finally, mapping mutations to identify the affected gene. The experiments in this proposal will provide new mutant strains, a resource for the entire zebrafish community, identify potentially novel genes, and uncover their function in hair cell regeneration, and contribute to the development of treatments for human hearing and balance disorders