Ferrón Sacri R, Marqués-Torrejón M Angeles, Mira Helena, Flores Ignacio, Taylor Kerrie, Blasco María A, Fariñas Isabel
Departamento de Biología Celular and Centro de Investigación Biomédica en Red en Enfermedades Neurodegerativas, Universidad de Valencia, 46100 Burjassot, Spain.
J Neurosci. 2009 Nov 18;29(46):14394-407. doi: 10.1523/JNEUROSCI.3836-09.2009.
Proliferation in the subependymal zone (SEZ) and neurogenesis in the olfactory bulb decline in the forebrain of telomerase-deficient mice. The present work reveals additional effects of telomere shortening on neuronal differentiation, as adult multipotent progenitors with critically short telomeres yield reduced numbers of neurons that, furthermore, exhibit underdeveloped neuritic arbors. Genetic data indicate that the tumor suppressor protein p53 not only mediates the adverse effects of telomere attrition on proliferation and self-renewal but it is also involved in preventing normal neuronal differentiation of adult progenitors with dysfunctional telomeres. Interestingly, progenitor cells with short telomeres obtained from fetal brains do not exhibit any replicative defects but also fail to acquire a fully mature neuritic arbor, demonstrating cell cycle-independent effects of telomeres on neuronal differentiation. The negative effect of p53 on neuritogenesis is mechanistically linked to its cooperation with the Notch pathway in the upregulation of small GTPase RhoA kinases, Rock1 and Rock2, suggesting a potential link between DNA damage and the Notch signaling pathway in the control of neuritogenesis. We also show that telomerase expression is downregulated in the SEZ of aging mice leading to telomere length reductions in neurosphere-forming cells and deficient neurogenesis and neuritogenesis. Our results suggest that age-related deficits could be caused partly by dysfunctional telomeres and demonstrate that p53 is a central modulator of adult neurogenesis, regulating both the production and differentiation of postnatally generated olfactory neurons.
端粒酶缺陷小鼠前脑中，室管膜下区（SEZ）的细胞增殖及嗅球中的神经发生均有所减少。目前的研究揭示了端粒缩短对神经元分化的额外影响，因为端粒严重缩短的成年多能祖细胞产生的神经元数量减少，而且这些神经元的神经树突发育不全。遗传数据表明，肿瘤抑制蛋白p53不仅介导端粒磨损对增殖和自我更新的不利影响，还参与阻止端粒功能异常的成年祖细胞进行正常的神经元分化。有趣的是，从胎脑中获取的端粒短的祖细胞没有表现出任何复制缺陷，但也无法形成完全成熟的神经树突，这表明端粒对神经元分化具有不依赖细胞周期的影响。p53对神经突发生的负面影响在机制上与其在小GTP酶RhoA激酶Rock1和Rock2上调中与Notch信号通路的协同作用有关，这表明DNA损伤与Notch信号通路在神经突发生控制中存在潜在联系。我们还表明，衰老小鼠SEZ中的端粒酶表达下调，导致形成神经球的细胞中端粒长度缩短，神经发生和神经突发生不足。我们的结果表明，与年龄相关的缺陷可能部分由功能异常的端粒引起，并证明p53是成年神经发生的核心调节因子，调节出生后产生的嗅觉神经元的产生和分化。
