Gene disruption of p27 ^Kip1 allows cell proliferation in the postnatal and adult organ of Corti

TLDR

Hearing loss commonly results from hair‑cell degeneration, and in the mammalian organ of Corti supporting cells are terminally differentiated and express high levels of cyclin‑dependent kinase inhibitors, preventing regeneration. Disruption of the cyclin‑dependent kinase inhibitor p27^Kip1 in supporting cells induces proliferation in the postnatal and adult organ of Corti, indicating that relieving p27^Kip1‑mediated arrest can enable hair‑cell regeneration.

Abstract

Hearing loss is most often the result of hair-cell degeneration due to genetic abnormalities or ototoxic and traumatic insults. In the postembryonic and adult mammalian auditory sensory epithelium, the organ of Corti, no hair-cell regeneration has ever been observed. However, nonmammalian hair-cell epithelia are capable of regenerating sensory hair cells as a consequence of nonsensory supporting-cell proliferation. The supporting cells of the organ of Corti are highly specialized, terminally differentiated cell types that apparently are incapable of proliferation. At the molecular level terminally differentiated cells have been shown to express high levels of cell-cycle inhibitors, in particular, cyclin-dependent kinase inhibitors [Parker, S. B., et al . (1995) Science 267, 1024–1027], which are thought to be responsible for preventing these cells from reentering the cell cycle. Here we report that the cyclin-dependent kinase inhibitor p27 Kip1 is selectively expressed in the supporting-cell population of the organ of Corti. Effects of p27 Kip1 -gene disruption include ongoing cell proliferation in postnatal and adult mouse organ of Corti at time points well after mitosis normally has ceased during embryonic development. This suggests that release from p27 Kip1 -induced cell-cycle arrest is sufficient to allow supporting-cell proliferation to occur. This finding may provide an important pathway for inducing hair-cell regeneration in the mammalian hearing organ.