Gene disruption of p27(Kip1) allows cell proliferation in the postnatal and adult organ of corti.
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.
Löwenheim
H
H
Department of Otolaryngology, University of Tübingen, Silcherstrasse 5, 72076 Tübingen, Germany. hubert.loewenheim@uni-tuebingen.de
Furness
D N
DN
Kil
J
J
Zinn
C
C
Gültig
K
K
Fero
M L
ML
Frost
D
D
Gummer
A W
AW
Roberts
J M
JM
Rubel
E W
EW
Hackney
C M
CM
Zenner
H P
HP
D000161:Acoustic Stimulation; D000375:Aging / Q000502:physiology; D000818:Animals; D001309:Auditory Threshold; D001933:Brain Stem / Q000502:physiology; D018797:Cell Cycle Proteins; D002455:Cell Division; D003051:Cochlea / Q000254:growth & development / Q000502:physiology / Q000648:ultrastructure; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005314:Embryonic and Fetal Development; D004791:Enzyme Inhibitors / Q000378:metabolism; D016057:Evoked Potentials, Auditory, Brain Stem; D018507:Gene Expression Regulation, Developmental; D006198:Hair Cells, Auditory / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008938:Mitosis; D009416:Nerve Regeneration; D009925:Organ of Corti / Q000166:cytology / Q000254:growth & development / Q000502:physiology*; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27