The Cyclin Dependent Kinase Inhibitor p27Kip1 Maintains Terminal Differentiation in the Mouse Organ of Corti

Abstract

Background: In mammals, sensory hair cells and supporting cells that comprise the auditory epithelium (i.e. organ of Corti) lose the ability to proliferate or regenerate after embryogenesis and are considered terminally differentiated. Previously, it was demonstrated that deletion of p27 Kip1 , a cyclin dependent kinase inhibitor, extends the period of cellular proliferation beyond embryogenesis in the organ of Corti, resulting in supernumary supporting cells and hair cells. Methodology/Principle Findings: We now report that p27 deletion results in an increased number of inner and outer hair cells at one month of age. These hair cells display normal phenotypes including uptake of AM1-43, a mechanotransduction dye. Outer Hair Cells (OHCs) in the p27-/-cochlea appropriately express Prestin, the cellular protein essential for OHC electromotility. This has not been observed in new hair cells induced by deletion of Rb or over expression of Atoh1. Ototoxic antibiotics (aminoglycosides) can cause hair cell loss resulting in hearing loss. In p27 Kip1 +/-and -/-mice, aminoglycosides induce de novo supporting cell proliferation and hair cell regeneration. Thus, in addition to mediating cell cycle withdrawal during embryogenesis, p27 blocks cycle re-entry after embryogenesis and maintains the terminally differentiated state in the organ of Corti. In p27 Kip1 +/-and -/-mice, Cyclin E expression was observed in supporting cells on postnatal day 0, increased in expression by postnatal day 7 and was maintained into adulthood. Following p27 inhibition, Cyclin E expression in supporting cells is presumed to drive cell cycle re-entry. Conclusions/Significance: We propose that CyclinE is the dominant cyclin in the supporting cells and release from p27 inhibition allows supporting cell to proliferation and hair cell regeneration.