Cell cycle regulation in the inner ear sensory epithelia: role of cyclin D1 and cyclin-dependent kinase inhibitors.
Sensory hair cells and supporting cells of the mammalian cochlea and vestibular (balance) organs exit the cell cycle during embryogenesis and do not proliferate thereafter. Here, we have studied the mechanisms underlying the maintenance of the postmitotic state and the proliferative capacity of these cells. We provide the first evidence of the role of cyclin D1 in cell cycle regulation in these cells. Cyclin D1 expression disappeared from embryonic hair cells as differentiation started. The expression was transiently upregulated in cochlear hair cells early postnatally, paralleling the spatiotemporal pattern of unscheduled cell cycle re-entry of cochlear hair cells from the p19(Ink4d)/p21(Cip1) compound mutant mice. Cyclin D1 misexpression in vitro in neonatal vestibular HCs from these mutant mice triggered S-phase re-entry. Thus, cyclin D1 suppression is important for hair cell's quiescence, together with the maintained expression of cyclin-dependent kinase inhibitors. In contrast to hair cells, cyclin D1 expression was maintained in supporting cells when differentiation started. The expression continued during the neonatal period when supporting cells have been shown to re-enter the cell cycle upon stimulation with exogenous mitogens. Thereafter, the steep decline in supporting cell's proliferative activity paralleled with cyclin D1 downregulation. Thus, cyclin D1 critically contributes to the proliferative plasticity of supporting cells. These data suggest that targeted cyclin D1 induction in supporting cells might be an avenue for proliferative regeneration in the inner ear.
Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
Heidi
H
Laine
Marilin
M
Sulg
Anna
A
Kirjavainen
Ulla
U
Pirvola
D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D003051:Cochlea / Q000737:chemistry; D019938:Cyclin D1 / Q000502:physiology*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000502:physiology*; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000032:analysis / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis / Q000502:physiology; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000032:analysis / Q000502:physiology; D007758:Ear, Inner / Q000196:embryology*; D006198:Hair Cells, Auditory / Q000166:cytology*; D019394:Ki-67 Antigen / Q000032:analysis; D051379:Mice; D015398:Signal Transduction; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000502:physiology
C495267:CTNNB1 protein, mouse; C530105:Ccnd1 protein, mouse; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; C493965:Cdkn1c protein, mouse; C493975:Cdkn2d protein, mouse; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050764:Cyclin-Dependent Kinase Inhibitor p19; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050761:Cyclin-Dependent Kinase Inhibitor p57; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27