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The Journal of Neuroscience, February 7, 2007, 27(6):1434-1444; doi:10.1523/JNEUROSCI.4956-06.2007

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Development/Plasticity/Repair
p19^Ink4d and p21^Cip1 Collaborate to Maintain the Postmitotic State of Auditory Hair Cells, Their Codeletion Leading to DNA Damage and p53-Mediated Apoptosis

Heidi Laine,¹ Angelika Doetzlhofer,³ Johanna Mantela,¹ Jukka Ylikoski,¹ Marikki Laiho,² Martine F. Roussel,⁴ Neil Segil,³ and Ulla Pirvola¹

¹Institute of Biotechnology and ²Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland, ³Gonda Department of Cell and Molecular Biology, House Ear Institute, Los Angeles, California 90057, and ⁴Department of Tumor Biology and Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Correspondence should be addressed to Ulla Pirvola, Institute of Biotechnology, University of Helsinki, P.O. Box 56, Viikinkaari 9, 00014 Helsinki, Finland. Email: ulla.pirvola{at}helsinki.fi

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.

Key words: cyclin-dependent kinase inhibitor; proliferation; DNA damage; apoptosis; development; inner ear

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Received Aug. 15, 2006; revised Dec. 22, 2006; accepted Dec. 22, 2006.

Correspondence should be addressed to Ulla Pirvola, Institute of Biotechnology, University of Helsinki, P.O. Box 56, Viikinkaari 9, 00014 Helsinki, Finland. Email: ulla.pirvola{at}helsinki.fi

This article has been cited by other articles:

				M. Schwander, W. Xiong, J. Tokita, A. Lelli, H. M. Elledge, P. Kazmierczak, A. Sczaniecka, A. Kolatkar, T. Wiltshire, P. Kuhn, et al. From the Cover: A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells PNAS, March 31, 2009; 106(13): 5252 - 5257. [Abstract] [Full Text] [PDF]

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