RT Journal Article
SR Electronic
T1 p19<sup>Ink4d</sup> and p21<sup>Cip1</sup> Collaborate to Maintain the Postmitotic State of Auditory Hair Cells, Their Codeletion Leading to DNA Damage and p53-Mediated Apoptosis
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1434
OP 1444
DO 10.1523/JNEUROSCI.4956-06.2007
VO 27
IS 6
A1 Heidi Laine
A1 Angelika Doetzlhofer
A1 Johanna Mantela
A1 Jukka Ylikoski
A1 Marikki Laiho
A1 Martine F. Roussel
A1 Neil Segil
A1 Ulla Pirvola
YR 2007
UL http://www.jneurosci.org/content/27/6/1434.abstract
AB 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) p19Ink4d 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, p21Cip1, on cell cycle reactivation. The codeletion of p19Ink4d and p21Cip1 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.