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.