Musashi1 and miR-137 antagonism: impact on neurogenesis and diseases

成人神经发生是大脑功能的基础，在记忆和修复中起着重要作用。在.期间 神经发生，戏剧性的生理和形态变化是由于协调变化 由特定的调节器驱动的基因表达。调节失调最终会导致修复减少， 神经退行性疾病和脑肿瘤的发展。我们发现了以Musashi1和miR-137为核心的自我更新和分化之间的分子开关。这些监管者有相反的看法 表达模式和功能。Musashi1(Msi1)是一种与自我更新有关的干细胞蛋白，而miR-137则是一种神经源性miRNA。MSI1和miR-137在两个不同的水平上相互作用。首先，miR-137抑制了 Msi1。其次，基因组分析显示，Msi1和miR-137以相反的方向调节一大套 涉及细胞迁移、神经元分化和细胞形态发生的靶基因。 我们认为Msi1和miR-137之间的平衡是决定细胞命运的关键因素。在我们的 拮抗模型，Msi1主要通过增加与miR-137共享的靶点的表达来促进自我更新，而miR-137通过双重负开关来驱动分化，抑制Msi1及其共享的靶 目标。 在目标1中，我们将使用基因组分析来构建Msi1和miR-137的扩展调控网络。我们 将(通过监管、功能或遗传关联)在共享的MSI1/miR-137和 在神经发生过程中显示表达变化的其他基因的独特靶点和识别其他调控因子 它们有可能成为Msi1和miR-137的合作伙伴。在目标2中，我们将调查与以下内容相关的两个场景 阿尔茨海默病和胶质母细胞瘤的发展：1)Msi1抑制对miR-137在分化中的作用至关重要，2) 如果需要miR-137的高表达来维持神经元的表型，以及3)如果msi1的增加 分化细胞中的表达可能触发细胞周期重新进入和抑制维持细胞周期的基因 神经元表型。接下来，为了进一步支持我们的拮抗模型，我们将检查miR-137是否受到抑制 增加海马神经元Msi1的表达，如果miR-137抑制引发的改变可以 通过使Msi1保持沉默来“中和”。

Adult neurogenesis is fundamental to brain function with important roles in memory and repair. During neurogenesis, dramatic physiological and morphological alterations take place due to coordinated changes in gene expression driven by specific regulators. Dysregulation can ultimately lead to reduced repair, neurodegenerative diseases and brain tumor development. We identified a molecular switch between self-renewal and differentiation having as central players Musashi1 and miR-137. These regulators have opposite expression patterns and functions. Musashi1 (Msi1) is a stem-cell protein implicated in self-renewal while miR-137 functions as a neurogenic miRNA. Msi1 and miR-137 interact at two different levels. First, miR-137 represses Msi1. Second, genomic analyses revealed that Msi1 and miR-137 regulate in opposite directions a large set of target genes implicated in cell migration, neuronal differentiation and cell morphogenesis. We propose that the balance between Msi1 and miR-137 is a key factor in cell fate decisions. In our antagonistic model, Msi1 promotes self-renewal mainly by increasing the expression of targets shared with miR-137 while miR-137 drives differentiation using a double negative switch, inhibiting Msi1 and also the their shared targets. In Aim 1, we will use genomic analyses to build an extended regulatory network for Msi1 and miR-137. We will establish connections (via regulatory, functional or genetic associations) between Msi1/miR-137 shared and unique targets to other genes displaying changes in expression during neurogenesis and identify other regulators that potentially function as partners of Msi1 and miR-137. In Aim 2, we will investigate two scenarios relevant to Alzheimer’s and glioblastoma development: 1) Msi1 inhibition is critical to miR-137 function in differentiation, 2) if miR-137 high expression is required to maintain the neuronal phenotype and 3) if an increase in Msi1 expression in differentiated cells could trigger cell cycle re-entry and repression of genes that maintain the neuronal phenotype. Next, to further support our model of antagonism, we will check if inhibition of miR-137 increases Msi1 expression in hippocampal neurons and if the alterations triggered by miR-137 inhibition can be “neutralized” by silencing Msi1.