Sage Cyrille, Huang Mingqian, Vollrath Melissa A, Brown M Christian, Hinds Philip W, Corey David P, Vetter Douglas E, Chen Zheng-Yi
Neurology Service, Center for Nervous System Repair, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A. 2006 May 9;103(19):7345-50. doi: 10.1073/pnas.0510631103. Epub 2006 Apr 28.
The retinoblastoma protein pRb is required for cell-cycle exit of embryonic mammalian hair cells but not for their early differentiation. However, its role in postnatal hair cells is unknown. To study the function of pRb in mature animals, we created a new conditional mouse model, with the Rb gene deleted primarily in the inner ear. Progeny survive up to 6 months. During early postnatal development, pRb(-/-) hair cells continue to divide and can transduce mechanical stimuli. However, adult pRb(-/-) mice exhibit profound hearing loss due to progressive degeneration of the organ of Corti. We show that pRb is required for the full maturation of cochlear outer hair cells, likely in a gene-specific manner, and is also essential for their survival. In addition, lack of pRb results in cell division in postnatal auditory supporting cells. In contrast, many pRb(-/-) vestibular hair cells survive and continue to divide in adult mice. Significantly, adult pRb(-/-) vestibular hair cells are functional, and pRb(-/-) mice maintain partial vestibular function. Therefore, the functional adult vestibular pRb(-/-) hair cells, derived from proliferation of postnatal hair cells, are largely integrated into vestibular pathways. This study reveals essential yet distinct roles of pRb in cochlear and vestibular hair cell maturation, function, and survival and suggests that transient block of pRb function in mature hair cells may lead to propagation of functional hair cells.
视网膜母细胞瘤蛋白pRb是胚胎哺乳动物毛细胞退出细胞周期所必需的，但不是其早期分化所必需的。然而，它在出生后毛细胞中的作用尚不清楚。为了研究pRb在成熟动物中的功能，我们创建了一种新的条件性小鼠模型，其中Rb基因主要在内耳中缺失。后代存活至6个月。在出生后早期发育过程中，pRb(-/-)毛细胞继续分裂并能转导机械刺激。然而，成年pRb(-/-)小鼠由于柯蒂氏器的进行性退化而表现出严重的听力损失。我们表明，pRb是耳蜗外毛细胞完全成熟所必需的，可能是以基因特异性方式，并且对其存活也至关重要。此外，缺乏pRb会导致出生后听觉支持细胞的细胞分裂。相比之下，许多pRb(-/-)前庭毛细胞在成年小鼠中存活并继续分裂。值得注意的是，成年pRb(-/-)前庭毛细胞是有功能的，并且pRb(-/-)小鼠维持部分前庭功能。因此，源自出生后毛细胞增殖的成年功能性pRb(-/-)前庭毛细胞在很大程度上整合到前庭通路中。这项研究揭示了pRb在耳蜗和前庭毛细胞成熟、功能和存活中的重要但不同的作用，并表明成熟毛细胞中pRb功能的短暂阻断可能导致功能性毛细胞的增殖。
