Age-Dependent Muller Glia Neurogenic Competence in the Mouse Retina
Age-Dependent Muller Glia Neurogenic Competence in the Mouse Retina
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DOI：
10.1002/glia.22846
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发表时间：
2015-10-01
期刊：
影响因子：
6.2
通讯作者：
Karl, Mike O.
中科院分区：
文献类型：
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作者：
Loeffler, Kati;Schaefer, Patrick;Karl, Mike O.
限制哺乳动物神经元再生的机制及其与反应性神经胶质增生的关系尚不清楚。米勒神经胶质（MG），常见于所有脊椎动物视网膜，很容易再生神经元损失在一些物种，但通常不是在哺乳动物。然而，已经报道了有限的哺乳动物视网膜再生的实验刺激。在这里，我们使用小鼠视网膜器官培养的方法来调查MG反应在不同的小鼠年龄。我们发现，MG进行定义的时空变化后，刺激。在EGF刺激的青少年有丝分裂后视网膜，大多数MG上调细胞周期调节因子（Mcm 6，Pcna，Ki 67，Ccnd 1）在48小时内离体;一些还表达的神经原性因子Ascl 1，Pax 6，和Vsx 2;高达60%重新进入细胞周期，其中一些分层分裂主要是顶端;和大多数刺激后停止增殖。MG后代的亚群开始表达转录因子（Ptf 1a，Nr 4a 2）和神经元（Calb 1，Calb 2，Rbfox 3），但不表达神经胶质标记物，表明神经发生。BrdU追踪，遗传谱系追踪，和转基因报告实验表明，MG重编程到神经源性阶段和增殖，一些MG后代分化成神经元样细胞，最有可能无长突，没有光感受器;大多数其他人保持在去分化状态。小鼠MG再生潜力变得受限，取决于动物的年龄，如通过细胞周期和神经原性因子的有限激活所观察到的。小鼠MG的阶段依赖性分析揭示了相似性和差异相比，MG衍生的再生鱼和小鸡。因此，小鼠视网膜离体方法是一种潜在的分析，用于理解和克服哺乳动物MG衍生的神经元再生的局限性。离体小鼠视网膜中的有丝分裂后MG可以被刺激增殖，表达神经源性因子，并产生表达神经元或神经胶质标记物的后代。这种潜在的再生能力随着小鼠年龄的增加而变得有限。
The mechanisms limiting neuronal regeneration in mammals and their relationship with reactive gliosis are unknown. Muller glia (MG), common to all vertebrate retinas, readily regenerate neuron loss in some species, but normally not in mammals. However, experimental stimulation of limited mammalian retina regeneration has been reported. Here, we use a mouse retina organ culture approach to investigate the MG responses at different mouse ages. We found that MG undergo defined spatio-temporal changes upon stimulation. In EGF-stimulated juvenile postmitotic retinas, most MG upregulate cell-cycle regulators (Mcm6, Pcna, Ki67, Ccnd1) within 48 h ex vivo; some also express the neurogenic factors Ascl1, Pax6, and Vsx2; up to 60% re-enter the cell cycle, some of which delaminate to divide mostly apically; and the majority cease to proliferate after stimulation. A subpopulation of MG progeny starts to express transcription factors (Ptf1a, Nr4a2) and neuronal (Calb1, Calb2, Rbfox3), but not glial, markers, indicating neurogenesis. BrdU-tracking, genetic lineage-tracing, and transgenic-reporter experiments suggest that MG reprogram to a neurogenic stage and proliferate; and that some MG progeny differentiate into neuronal-like cells, most likely amacrines, no photoreceptors; most others remain in a de-differentiated state. The mouse MG regeneration potential becomes restricted, dependent on the age of the animal, as observed by limited activation of the cell cycle and neurogenic factors. The stage-dependent analysis of mouse MG revealed similarities and differences when compared with MG-derived regeneration in fish and chicks. Therefore, the mouse retina ex vivo approach is a potential assay for understanding and overcoming the limitations of mammalian MG-derived neuronal regeneration. Postmitotic MG in mouse retina ex vivo can be stimulated to proliferate, express neurogenic factors, and generate progeny expressing neuronal or glial markers. This potential regenerative competence becomes limited with increasing mouse age.