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

在成年哺乳动物大脑中，神经干细胞(NSCs)在其他神经胶质形成环境中仅限于少数神经源性壁龛。因此，重要的是要了解调控神经元维持和神经起源谱系发展的分子机制，作为成年哺乳动物大脑如何产生神经元的主要范例。我们对成体室管膜下区(SEZ)神经干细胞的全基因组表达分析揭示了神经源性启动的现象，即神经源性命运决定因子在NSCs中的低水平表达，但没有检测到蛋白水平。因此，这种低水平的表达为神经干细胞走向神经发生做好了准备，但仍然允许多潜能，并且不会过早地将这些细胞分化为具有更高mRNA和蛋白质水平的神经元前体细胞。在这里，我们的目标是研究分子基础，a)维持这种启动状态，b)当神经母细胞从神经干细胞中出现时，提高表达和蛋白质水平。我们对NSCs及其后代的转录组分析发现，几个microRNAs(MiRNAs)是前一个过程(A)的候选者，几个长的非编码RNAs(LncRNAs)是(B)的候选者。我们建议在这一提议中测试我们的模型，在该模型中，特定的miRNAs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，所提出的成人干细胞谱系启动调控多能性和谱系进展的非编码RNA功能模型可能对神经系统以外的成人干细胞具有更广泛的相关性，因此在这一优先计划的框架内进行研究具有很高的相关性。

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.