Wnt pathway mutations alter hair cell regeneration in the zebrafish fish lateral line

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Abstract Debilitating hear loss affects over 6% of the world’s population and can result in a profound decrease in the quality of life for those afflicted. Hearing is mediated by mechanosensory hair cells located in the cochlea of the inner ear. Another population of hair cells in the inner ear makes up the vestibular system to relay the sensation of balance and gravity. Hair cell damage results in sensory defects. The causes of hair cell damage include age, noise exposure, ototoxic drugs, disease, and injury. In adult mammals, once hair cells are lost, they do not regenerate, resulting in permanent hearing loss and balance disorders. In addition to mediating the sensations of hearing and balance, mechanosensory hair cells are also required for close touch sensation in the lateral line systems of aquatic vertebrates. Lateral line hair cells are morphologically and genetically very similar to inner ear hair cells. In contrast to the inner ear hair cell of mammals, the hair cells of the lateral line system are robustly regenerative. The zebrafish (Danio rerio), has emerged as a valuable model to study the mechanisms of mechanosensory hair cell regeneration. Research using pharmacological manipulation of the canonical Wnt pathway suggests that it is critical for regulating the cellular proliferation and differentiation required for hair cell regeneration. To genetically confirm a role for Wnt signaling during regeneration, we will use three zebrafish lines carrying mutations at different points in the Wnt pathway. In Aim 1, we will characterize hair cell regeneration in the krm1nl10 mutant, which results in overactivation of Wnt signaling. In Aim 2, we will characterize regeneration in the lef1nl2 mutant line, which results in an inhibition of Wnt activity. In Aim 3, we will examine regeneration in a third line, foxg1aa266, which contains a mutation in the Wnt transcriptional target gene foxg1a. Together, we will use these lines to determine how cellular proliferation, differentiation, and survival are regulated by the Wnt pathway during regeneration of mechanosensory hair cells. The long-term goal of this work is to provide a mechanism for regenerate hair cells in the human inner ear.