Mechanosensory transduction via intact hair cells is necessary for auditory and vestibular perception and thus is central to survival and communication in many species. Mammals do not demonstrate the capacity to regenerate hair cells post-embryologically. Thus, loss of hair cells leads to profound sensory deficits. In contrast, avian species produce vestibular hair cells continually throughout their life time, and they regenerate auditory and vestibular hair cells in response to damage. Avian hair cell regeneration occurs primarily by up-regulation of cell proliferation and differentiation of postmitotic cells into hair cells. These processes occur spontaneously in cultured avian inner ear epithelia. In cultured mammalian vestibular organs, some mitosis is stimulated by exogenous growth factors, suggesting that mammalian hair cell progenitors also have the capacity to divide. However, there is little experimental evidence that, in mammals, postmitotic cells are able to differentiate into hair cells. The broad goals of my research are to understand the cellular and molecular events that regulate hair cell production in the post-hatch chick and to apply this knowledge to eventually stimulate hair cell regeneration in mammals. The proposed experiments will use in vivo and in vitro approaches to identify molecules that regulate hair cell regeneration in the posthatch chick. Although several groups currently focus on events regulating mitosis of mature support cells in avian auditory and vestibular epithelia, relatively few studies are aimed at understanding how postmitotic cells are instructed to become hair cells. I will examine the role of intercellular signaling via the transforming growth factor beta (TGF()superfamily and via delta and serrate in the regulation of hair cell differentiation in the mature avian inner ear. Initial experiments will examine changes in receptor and ligand genes associated with these pathways in control and damaged avian hair cell epithelia. TGF(-related molecules that show changes in expression during regeneration will be added to cultured avian hair cell progenitors and infused into the intact avian inner ear to determine if they stimulate hair cell differentiation. If changes in delta and serrate expression accompany regeneration, I will examine the role of notch signaling in hair cell differentiation by perturbing notch expression in cultured avian hair cell progenitors. An understanding of how hair cell differentiation is regulated in mature vertebrates may lead to insight into the causes of congenital deafness and to therapeutic methods for curing hearing deficits.
