Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing
Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing
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DOI：
10.1038/nature05091
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发表时间：
2006-09-28
期刊：
影响因子：
64.8
通讯作者：
Morrison, Sean J.
中科院分区：
文献类型：
--
作者：
Molofsky, Anna V.;Slutsky, Shalom G.;Morrison, Sean J.
哺乳动物衰老与含有干细胞的组织再生能力降低有关（1，2）。有人提出，这至少部分是由祖细胞随着年龄的衰老引起的（3，4）;然而，尚未测试与衰老相关的基因是否在功能上有助于祖细胞活性的生理下降。在这里，我们表明，祖细胞增殖室管膜下区和嗅球中的神经发生，以及多能祖细胞的频率和自我更新的潜力，都随着年龄的增长在小鼠前脑下降。这些祖细胞频率和功能的下降与p16（INK 4a）表达的增加相关，p16编码与衰老相关的细胞周期蛋白依赖性激酶抑制剂（5）。衰老的p16（INK 4a）缺陷小鼠表现出明显较小的下降，脑室下区增殖，嗅球神经发生，多能祖细胞的频率和自我更新潜力。p16（INK 4a）缺陷并没有明显影响齿状回或肠神经系统中的祖细胞功能，表明在衰老过程中神经祖细胞对p16（INK 4a）表达增加的反应存在区域差异。因此，在衰老过程中，脑室下区祖细胞功能和嗅球神经发生的下降部分是由p16（INK 4a）表达增加引起的。
Mammalian ageing is associated with reduced regenerative capacity in tissues that contain stem cells(1,2). It has been proposed that this is at least partially caused by the senescence of progenitors with age(3,4); however, it has not yet been tested whether genes associated with senescence functionally contribute to physiological declines in progenitor activity. Here we show that progenitor proliferation in the subventricular zone and neurogenesis in the olfactory bulb, as well as multipotent progenitor frequency and self-renewal potential, all decline with age in the mouse forebrain. These declines in progenitor frequency and function correlate with increased expression of p16(INK4a), which encodes a cyclin-dependent kinase inhibitor linked to senescence(5). Ageing p16(INK4a)-deficient mice showed a significantly smaller decline in subventricular zone proliferation, olfactory bulb neurogenesis, and the frequency and self-renewal potential of multipotent progenitors. p16(INK4a) deficiency did not detectably affect progenitor function in the dentate gyrus or enteric nervous system, indicating regional differences in the response of neural progenitors to increased p16(INK4a) expression during ageing. Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16(INK4a) expression.