Cell cycle regulation in the inner ear sensory epithelia: Role of cyclin D1 and cyclin-dependent kinase inhibitors
Cell cycle regulation in the inner ear sensory epithelia: Role of cyclin D1 and cyclin-dependent kinase inhibitors
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DOI：
10.1016/j.ydbio.2009.10.027
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发表时间：
2010-01-01
影响因子：
2.7
通讯作者：
Pirvola, Ula
中科院分区：
文献类型：
--
作者：
Laine, Heidi;Sulg, Marilin;Pirvola, Ula
哺乳动物耳蜗和前庭（平衡）器官的感觉毛细胞和支持细胞在胚胎发生期间退出细胞周期，此后不再增殖。在这里，我们研究了这些细胞的有丝分裂后状态和增殖能力的维持机制。我们提供了第一个证据的细胞周期蛋白D1在这些细胞的细胞周期调控的作用。胚胎毛细胞分化开始时，细胞周期蛋白D1表达消失。该表达在出生后早期耳蜗毛细胞中瞬时上调，平行于p19（Ink 4d）/p21（CiP 1）复合突变小鼠耳蜗毛细胞非预定细胞周期再进入的时空模式。细胞周期蛋白D1在体外的错误表达在新生儿前庭毛细胞从这些突变小鼠触发S期再进入。因此，细胞周期蛋白D1的抑制是重要的毛细胞的静止，以及维持表达的细胞周期蛋白依赖性激酶抑制剂。与毛细胞相反，细胞周期蛋白D1的表达维持在支持细胞分化开始时。在新生儿期，当支持细胞被证明在用外源性有丝分裂原刺激后重新进入细胞周期时，表达继续。此后，支持细胞增殖活性的急剧下降伴随着细胞周期蛋白D1的下调。因此，细胞周期蛋白D1关键有助于支持细胞的增殖可塑性。这些数据表明，有针对性的细胞周期蛋白D1诱导支持细胞可能是一种途径，在内耳增殖再生。(C)2009 Elsevier Inc. All rights reserved.
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. (C) 2009 Elsevier Inc. All rights reserved.