Proliferation in the auditory receptor epithelium mediated by a cyclic AMP–dependent signaling pathway

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Abstract
Loss of receptor hair cells in the cochlea accounts for a significant proportion of hearing impairment in the population. Hair cells can be lost as a consequence of viral or bacterial insult, aging, and damage from intense sound or aminoglycoside antibiotics. The generation of replacement hair cells following damage by sound or drugs has been clearly demonstrated in birds; the chick is the best-studied model for auditory hair cell regeneration. New hair cells arise as progeny from an otherwise nondividing supporting cell population induced to proliferate by the damage. Functional recovery of hearing accompanies this cellular recovery process. The signals and pathways responsible for regenerative proliferation are unknown. Here we show that proliferation is induced in the undamaged receptor epithelium by agents that increase cyclic AMP levels, and that following this stimulation hair cells become labeled with proliferation markers. This remarkable proliferative response is blocked by inhibitors of the cAMP-regulated protein kinase A (PKA). In addition we show that the proliferative response induced by in vitro gentamicin damage is also significantly blocked by PKA inhibitors. These observations are the first to identify a signaling pathway that plays a role in regenerative proliferation in the auditory receptor epithelium.