The role of non-coding RNAs in maintenance of adult neural stem cellsand the regulation of neurogenesis

非编码RNA在成体神经干细胞维持和神经发生调节中的作用

• 批准号: 255316155
• 负责人: Professorin Dr. Magdalena Götz
• 金额: --
• 依托单位: Institut für Physiologische Genomik
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/255316155?language=en
• 关键词: role; non; coding; RNAs; maintenance

Neural stem cells (NSCs) are restricted to few neurogenic niches in the otherwise gliogenic environment in the adult mammalian brain. It is thus important to understand the molecular mechanisms regulating their maintenance and neurogenic lineage progression as a prime paradigm of how neurons can be generated in an adult mammalian brain. Our genome-wide expression analysis of NSCs from the adult subependymal zone (SEZ) revealed the phenomenon of neurogenic priming, i.e. expression of neurogenic fate determinants at low level with no detectable protein levels in the NSCs. This low level expression thus primes the NSCs towards neurogenesis, but still allows multipotency and does not prematurely differentiate these cells into neuronal progenitors that have much higher mRNA and protein levels. Here we aim to examine the molecular basis a) maintaining this priming state and b) raising expression and protein levels when neuroblasts emerge from the NSCs. Our analysis of the transcriptome of NSCs and their progeny identified several microRNAs (miRNAs) as candidate for the former process (a) and several long non-coding RNAs (lncRNAs) as candidates for (b). We propose to test in this proposal our model in which specific miRNAs maintain the low expression of neurogenic fate determinants, thereby acting as guardians of premature up-regulation of neurogenic fate determinants and fine-tuning of neurogenesis. Taken together we believe that the proposed model of non-coding RNA function for adult stem cell lineage priming regulating multipotency and lineage progression may have broader relevance for adult stem cells beyond the nervous system and hence be highly relevant to examine within the framework of this priority program.

神经干细胞（NSC）仅限于成年哺乳动物大脑中胶质细胞生成环境中的少数神经源性微环境。因此，了解调节其维持和神经源性谱系进展的分子机制非常重要，作为成年哺乳动物大脑中神经元如何生成的主要范例。我们对成人室管膜下区 (SEZ) 的 NSCs 进行全基因组表达分析，揭示了神经源性启动现象，即神经源性命运决定子的表达水平较低，而 NSCs 中没有可检测到的蛋白质水平。因此，这种低水平的表达使 NSC 做好神经发生的准备，但仍然允许多能性，并且不会过早地将这些细胞分化成具有更高 mRNA 和蛋白质水平的神经元祖细胞。在这里，我们的目的是检查分子基础：a）维持这种启动状态，b）当神经母细胞从 NSC 中出现时提高表达和蛋白质水平。我们对 NSC 及其后代的转录组的分析确定了几种 microRNA (miRNA) 作为前一个过程 (a) 的候选者，以及几种长非编码 RNA (lncRNA) 作为 (b) 的候选者。我们建议在这个提案中测试我们的模型，其中特定的 miRNA 维持神经源性命运决定因素的低表达，从而充当神经源性命运决定因素过早上调和神经发生微调的守护者。综上所述，我们认为，所提出的成体干细胞谱系启动调节多能性和谱系进展的非编码RNA功能模型可能与神经系统以外的成体干细胞具有更广泛的相关性，因此与该优先计划框架内的检查高度相关。