Regulation of Mammalian Cochlear Regeneration by BMP4

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DESCRIPTION (provided by applicant): Sensorineural deafness affects nearly half of adults over the age of 50. Primarily, sensorineural deafness is caused by the accumulated loss of mechanosensory cells in the cochlea, the sensory hair cells, which differentiate during embryogenesis and are not replaced. Adult non-mammalian vertebrates, in contrast, can regenerate lost sensory hair cells, but the signals that permit regeneration in these animals are unknown. We wish to investigate signals that may regulate sensory hair cell differentiation in the post-natal mammalian cochlea, using a novel in vitro system. In this system mouse embryonic cochlear epithelial cells can survive, proliferate, and differentiate into sensory hair cells. We show here as preliminary data that purified neonatal supporting cells have the ability to re-enter the cell cycle and express sensory hair cell markers in this assay. Through trial and error, we have identified BMP4 as a potential negative regulator of cell cycle entry by supporting cells. This data is important for two reasons: first, BMP4 is expressed in the cochleae of both birds and mice, although in different populations; second, BMP4 is down-regulated in the regenerating avian cochlea, but probably not in mammals. Thus, our model provides a simple and testable hypothesis for why birds might regenerate, but mammals do not. We propose experiments to determine the mechanism by which BMP4 might inhibit proliferation, whether BMP4 also plays a role in sensory hair cell differentiation, and whether interfering with the BMP4 signaling pathway might promote regeneration in the mammalian cochlea in vitro. People lose their hearing as they get older because the vibration-sensing cells in their inner ears die. Birds naturally regenerate their vibration-sensing cells, and we think this process is regulated by a molecule called BMP4. We want to test this idea by changing BMP4 activity in cultures of mouse inner ear organs.