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Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d

Abstract

Maintenance of the post-mitotic state in the post-natal mammalian brain is an active process that requires the cyclin-dependent kinase inhibitors (CKIs) p19Ink4d (Ink4d) and p27Kip1 (Kip1)1. In animals with targeted deletions of both Ink4d and Kip1, terminally differentiated, post-mitotic neurons are observed to re-enter the cell cycle, divide and undergo apoptosis. However, when either Ink4d or Kip1 alone are deleted, the post-mitotic state is maintained, suggesting a redundant role for these genes in mature neurons1. In the organ of Corti — the auditory sensory epithelium of mammals — sensory hair cells and supporting cells become post-mitotic during embryogenesis2 and remain quiescent for the life of the animal. When lost as a result of environmental insult or genetic abnormality, hair cells do not regenerate, and this loss is a common cause of deafness in humans3. Here, we report that targeted deletion of Ink4d alone is sufficient to disrupt the maintenance of the post-mitotic state of sensory hair cells in post-natal mice. In Ink4d−/− animals, hair cells are observed to aberrantly re-enter the cell cycle and subsequently undergo apoptosis, resulting in progressive hearing loss. Our results identify a novel mechanism underlying a non-syndromic form of progressive hearing loss in mice.

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Figure 1: Progressive hair cell loss in Ink4d−/− post-natal animals.
Figure 2: Progressive hearing loss in Ink4d−/− animals.
Figure 3: Ink4d is essential for actively maintaining the post-mitotic state of hair cells.
Figure 4: Ink4d in the cochlear sensory primordium and differentiated hair cells.
Figure 5: Normal development of the organ of Corti in Ink4d−/− mice.

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Acknowledgements

We thank J. Zuo for helpful discussion, A.Groves, A. Bass and J. Johnson for comments on the manuscript, W. den Besten for developing the PCR protocol used for genotyping Ink4d mice, J. Llamos, W. Macmurra, S. Portillo and C. Meunier for assistance in animal care and genotyping, and B. Welch for graphics assistance. We also thank J. Roberts and M. Fero for the p27Kip1-mutant mice, and C. Petit and A. El-Amraoui for the anti-Myosin VIIa antibody used in this study. This work was supported by grants from the National Institutes of Health (to N.S., P.C. and M.F.R.), the American Lebanese-Syrian-associated Charities (ALSAC) of St Jude Children's Research Hospital (to M.F.R.) and the Oberkotter Foundation (to N.S.).

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Correspondence to Neil Segil.

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Chen, P., Zindy, F., Abdala, C. et al. Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d. Nat Cell Biol 5, 422–426 (2003). https://doi.org/10.1038/ncb976

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