p19^Ink4dand p21^Cip1Collaborate to Maintain the Postmitotic State of Auditory Hair Cells, Their Codeletion Leading to DNA Damage and p53-Mediated Apoptosis

Abstract

Sensory hair cells of the auditory organ are generated during embryogenesis and remain postmitotic throughout life. Previous work has shown that inactivation of the cyclin-dependent kinase inhibitor (CKI) p19(Ink4d) leads to progressive hearing loss attributable to inappropriate DNA replication and subsequent apoptosis of hair cells. Here we show the synergistic action of another CKI, p21(Cip1), on cell cycle reactivation. The codeletion of p19(Ink4d) and p21(Cip1) triggered profuse S-phase entry of auditory hair cells during a restricted period in early postnatal life, leading to the transient appearance of supernumerary hair cells. In addition, we show that aberrant cell cycle reentry leads to activation of a DNA damage response pathway in these cells, followed by p53-mediated apoptosis. The majority of hair cells were absent in adult cochleas. These data, together with the demonstration of changing expression patterns of multiple CKIs in auditory hair cells during the stages of early postnatal maturation, show that the maintenance of the postmitotic state is an active, tissue-specific process, cooperatively regulated by several CKIs, and is critical for the lifelong survival of these sensory cells.