Ngn1 inhibits astrogliogenesis through induction of miR-9 during neuronal fate specification.
Ngn1 inhibits astrogliogenesis through induction of miR-9 during neuronal fate specification.
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作者：
Zhao J;Lin Q;Kim KJ;Dardashti FD;Kim J;He F;Sun Y
据推测，前神经因子，神经原蛋白1（Ngn 1），同时激活神经原程序和抑制替代星形胶质细胞程序时，指定的神经元的命运。虽然Ngn 1基本上抑制了星形胶质细胞生成Jak-Stat通路的激活，但其潜在的分子机制尚不清楚。在这里，通过采用体内和体外的方法，我们报告说，Ngn 1结合到大脑富集的microRNA，miR-9的启动子，并激活其在神经发生过程中的表达。随后，我们的体外研究表明，miR-9直接靶向Lifr-beta，Il 6st（gp 130）和Jak 1的mRNA，以下调Jak-Stat通路的这些关键上游组分，实现Stat磷酸化的抑制，从而抑制星形胶质细胞的生成。这项研究揭示了Ngn 1在细胞命运规范过程中调制非编码RNA表观遗传调控。http://dx.doi.org/10.7554/eLife.06885.001大脑通过一个称为神经元的复杂细胞网络处理来自全身的信息。其他的脑细胞包括星形胶质细胞支持这个网络。神经元和星形胶质细胞都起源于同一组干细胞，它们首先在一个称为神经发生的过程中产生神经元，然后再转化为星形胶质细胞。一种叫做神经生成素1的蛋白质通过调节特定基因的活性来促进神经发生并抑制星形胶质细胞的形成。它通过与基因中一个叫做启动子的区域结合来实现这一点。一个被称为Jak-Stat通路的细胞通讯系统（或“信号通路”）是脑干细胞制造星形胶质细胞所必需的。先前的研究表明，当干细胞开始制造神经元时，神经生成素1以高水平存在，这导致Jak-Stat通路失活。然而，当干细胞开始制造星形胶质细胞时，神经生成素1的水平降低，Jak-Stat通路被激活。因此，这种信号通路充当从神经发生过渡到星形胶质细胞形成的开关，但目前尚不清楚它到底是如何工作的。当一个基因处于活跃状态时，它的DNA序列被复制，形成核糖核酸（RNA）分子。这些分子可以作为模板来组装蛋白质，即信使RNA。或者，它们可以被加工成另一种称为microRNA的RNA，它可以通过促进特定信使RNA的破坏来关闭特定基因的活性。Zhao等人研究了小鼠大脑中的神经发生，发现neurogenin 1可以直接结合到一个基因的启动子上，该基因可以产生一种称为miR-9的microRNA。实验表明，neurogenin 1增加了该基因的活性，使得在神经发生过程中脑干细胞中miR-9的量增加。反过来，这种microRNA降低了几个关键基因的活性，这些基因编码参与Jak-Stat途径的蛋白质。Zhao等人的发现揭示了神经生成素1通过调节miR-9的产生来促进神经发生并抑制星形胶质细胞的形成。Jak-Stat通路在神经损伤、神经修复和免疫系统中起着重要作用，因此靶向miR-9的药物可能有潜力开发成治疗影响神经系统疾病的新疗法。DOI：http://dx.doi.org/10.7554/eLife.06885.002网站
It has been postulated that a proneural factor, neurogenin 1 (Ngn1), simultaneously activates the neurogenic program and inhibits the alternative astrogliogenic program when specifying the neuronal fate. While Ngn1 substantially suppresses the activation of the astrogliogenic Jak-Stat pathway, the underlying molecular mechanism was unknown. Here, by employing in vivo and in vitro approaches, we report that Ngn1 binds to the promoter of a brain-enriched microRNA, miR-9, and activates its expression during neurogenesis. Subsequently, our in vitro study showed that miR-9 directly targets mRNAs of Lifr-beta, Il6st (gp130), and Jak1 to down-regulate these critical upstream components of the Jak-Stat pathway, achieving inhibition of Stat phosphorylation and consequently, suppression of astrogliogenesis. This study revealed Ngn1 modulated non-coding RNA epigenetic regulation during cell fate specifications. DOI: http://dx.doi.org/10.7554/eLife.06885.001 The brain processes information from all over the body through a complex network of cells called neurons. Other brain cells—including star-shaped cells called astrocytes—support this network. Both neurons and astrocytes originate from the same group of stem cells, which first give rise to neurons in a process called neurogenesis before they switch to producing astrocytes. A protein called neurogenin 1 promotes neurogenesis and suppresses the formation of astrocytes by regulating the activity of particular genes. It does so by binding to a region within the genes called the promoter. A cell communication system (or ‘signaling pathway’) known as the Jak-Stat pathway is required for brain stem cells to make astrocytes. Previous research has shown that neurogenin 1 is present at high levels when stem cells start to make neurons, which leads to the inactivation the Jak-Stat pathway. However, when stem cells start to make astrocytes, the levels of neurogenin 1 decrease and the Jak-Stat pathway is activated. This signaling pathway therefore acts as a switch for the transition from neurogenesis to the formation of astrocytes, but it is not clear exactly how it works. When a gene is active, its DNA sequence is copied to make molecules of ribonucleic acid (RNA). These molecules can be used as templates to assemble proteins—known as messenger RNAs. Alternatively, they may be processed to make another type of RNA called microRNA, which can switch off the activity of particular genes by promoting the destruction of particular messenger RNAs. Zhao et al. studied neurogenesis in the mouse brain and found that neurogenin 1 can directly bind to the promoter of a gene that makes a microRNA called miR-9. The experiments show that neurogenin 1 increases the activity of this gene so that the amount of miR-9 in brain stem cells increases during neurogenesis. In turn, this microRNA lowers the activity of several critical genes that encode proteins involved in the Jak-Stat pathway. Zhao et al.'s findings reveal that neurogenin 1 promotes neurogenesis and inhibits astrocyte formation by regulating the production of miR-9. The Jak-Stat pathway plays important roles in nerve injury, neural repair, and the immune system, so drugs that target miR-9 may have the potential to be developed into new therapies to treat diseases that affect the nervous system. DOI: http://dx.doi.org/10.7554/eLife.06885.002