Mature mice lacking Rbl2/p130 gene have supernumerary inner ear hair cells and supporting cells.
Mature mice lacking Rbl2/p130 gene have supernumerary inner ear hair cells and supporting cells.
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DOI：
10.1523/jneurosci.5821-10.2011
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发表时间：
2011-06-15
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影响因子：
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通讯作者：
Walsh EJ
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作者：
Rocha-Sanchez SM;Scheetz LR;Contreras M;Weston MD;Korte M;McGee J;Walsh EJ
成年哺乳动物听觉毛细胞（HC）及其相关支持细胞（SCs）不增殖，HC死亡导致不可逆的神经感觉听力丧失和平衡障碍。在非哺乳动物脊椎动物中，hc的缺失会诱导相邻非感觉SCs的有丝分裂增殖和/或直接SC转分化以产生替代细胞。这导致了非哺乳动物感觉系统的结构和功能恢复。长期以来，人们一直提出通过细胞移植或通过分子疗法转化现有细胞来替代哺乳动物听觉细胞。然而，具有明确治疗潜力的HC替代策略仍然难以捉摸。视网膜母细胞瘤（pRB）家族的细胞周期调节因子Rb1、Rbl1 （p107）和Rbl2 （p130）调节增殖细胞G1期到S期的转变。在内耳中，涉及pRBs，特别是p107和p130的生化和分子途径相对未被探索，其治疗适用性尚未确定。在这项研究中，我们分析了p130基因敲除（p130−/−）的成年小鼠耳蜗，发现缺乏p130基因会导致耳蜗顶端区域出现更多的hc和SCs。在p130−/−小鼠中没有观察到这些多余的SCs转分化为hcc的证据。然而，成人p130−/−耳蜗中SCs的非预定增殖与真正的细胞周期抑制剂的下调相结合，为p130作为耳蜗更顶端区域SC和HC有丝分裂静止的调节剂提供了机制基础。有趣的是，p130−/−小鼠表现出几乎正常的外周听觉敏感性。
Adult mammalian auditory hair cells (HCs) and their associated supporting cells (SCs) do not proliferate, and HC death leads to irreversible neurosensory hearing loss and balance impairment. In non-mammalian vertebrates, loss of HCs induces mitotic proliferation of adjacent non-sensory SCs and/or direct SC transdifferentiation to generate replacement cells. This results in the structural and functional recovery of the non-mammalian sensory systems. Potential replacement of mammalian auditory HCs, either by transplanting cells or by transforming existing cells through molecular therapy, has long been proposed. However, HC replacement strategies with clear therapeutic potential remain elusive. The retinoblastoma (pRB) family of cell cycle regulators, Rb1, Rbl1 (p107), and Rbl2 (p130), regulate the G1 to S phase transition in proliferating cells. In the inner ear, the biochemical and molecular pathways involving pRBs, particularly p107 and p130 are relatively unexplored and their therapeutic suitability is yet to be determined. In this study, we analyzed the cochleae of adult p130 knockout (p130−/−) mice and showed that lack of the p130 gene results in extra rows of HCs and SCs in the more apical regions of the cochlea. No evidence of transdifferentiation of these supernumerary SCs into HCs was observed in the p130−/− mouse. Nevertheless, unscheduled proliferation of SCs in the adult p130−/− cochlea coupled to downregulation of bona fide cell cycle inhibitors provides a mechanistic basis for p130’s role as a regulator of SC and HC mitotic quiescence in the more apical regions of the cochlea. Interestingly, p130−/− mice exhibited nearly normal peripheral auditory sensitivity.