Gene disruption of p27Kip1 allows cell proliferation in the postnatal and adult organ of Corti

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

^*Department of Otolaryngology, ^‖Section of Physiological Acoustics and Communication, University of Tübingen, Silcherstrasse 5, 72076 Tübingen, Germany; ^‡Department of Communication and Neuroscience, Keele University, Keele, Staffordshire ST5 5BG, United Kingdom; ^§Virginia Merrill Bloedel Hearing Research Center and Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, WA 98195; and ^**Department of Basic Sciences, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104

Edited by Richard F. Thompson, University of Southern California, Los Angeles, CA, and approved January 7, 1999 (received for review September 30, 1998)

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.

Footnotes

↵ † To whom reprint requests should be addressed. e-mail: hubert.loewenheim{at}uni-tuebingen.de.
↵ ¶ Present address: Otogene USA, Inc., 4010 Stone Way North, Suite 120, Seattle, WA 98103.
This paper was submitted directly (Track II) to the Proceedings Office.
ABBREVIATIONS:

IHC,

inner hair cell;

OHC,

outer hair cell;

SEM,

scanning electron microscopy;

TEM,

transmission electron microscopy;

ABR,

brainstem-evoked response audiometry