The roles of alcohol-inducible RNA-operons in the fetal brain

摘要 酒精滥用最具破坏性的后果之一是它对胎儿发育的致畸作用， 特别是在大脑的发育及其复杂电路的形成方面。这些是永久性的 酒精滥用造成的发育缺陷被称为胎儿酒精谱系障碍(FASD)。 最近的研究结果表明，胎儿酒精暴露会导致广泛的适应性 发育中的大脑皮层内基因表达的变化。这种协调的基因表达变化 主要受高度特异的转录因子和miRNAs调控。此外，最近关于萌芽的研究 酵母和果蝇已经证明，RNA结合蛋白协调调节转录后 对特定类型的mRNAs进行修饰，以响应快速的环境变化。这个转录后的 特定的mRNAs和RNA结合蛋白的调节复合体，称为RNA操纵子，被认为是 在细胞对环境和疾病的适应中起着重要作用。然而，RNA操纵子的反应 由于酒精暴露在哺乳动物的大脑中，目前还不清楚。 我们最近发现，RNA结合蛋白Rbm39在乙醇作用下上调 暴露在人类和小鼠胚胎皮质中。我们的初步数据显示， Rbm39是保护胚胎神经前体细胞免受细胞死亡和细胞周期停滞所必需的 小鼠大脑皮层暴露于乙醇。然而，Rbm39表达的变化，无论是由于- 功能，对正常大脑皮质发育无明显影响。这些结果表明，Rbm39 在酒精暴露中扮演特定的角色。此外，我们发现Rbm39调节 适应性细胞保护所需的特定mRNAs转录后修饰 乙醇。因此，我们假设Rbm39通过RNA来协调转录后修饰- 在接触乙醇后，操纵子，提供了一个即时和适应系统，以保护细胞内 胚胎皮质。我们将通过三个不同的目标来检验这一假设。 目标1将通过敲除胚胎中的Rbm39来定义Rbm39对神经保护的要求 大脑皮层暴露在乙醇中。目的2将确定外源Rbm39对RNA的活性是否增加- 操纵子可以进一步减少乙醇对大脑的损害。Aim3将检查Rbm39是否协调 特定基因的转录后立即修饰对酒精暴露的反应。

Summary One of the most devastating consequences of alcohol misuse is its teratogenic effects on fetal development, particularly in the development of the brain and the formation of its complex circuitry. These permanent developmental deficits caused by alcohol misuse are referred to as Fetal Alcohol Spectrum Disorder (FASD). Recent findings have demonstrated that fetal alcohol exposure results in wide-ranging and adaptive alterations of gene expression within the developing cerebral cortex. Such coordinated gene expression changes are regulated mainly by highly specified transcription factors and miRNAs. In addition, recent studies on budding yeast and fruit fly have demonstrated that RNA binding proteins coordinately regulate the post-transcriptional modification of specific types of mRNAs in response to rapid environmental changes. This post-transcriptional regulatory complex of specific mRNAs and RNA binding proteins, known as RNA-operons, are suggested to have important roles in cellular adaptation to environment and diseases. However, the response of RNA-operons as a result of alcohol exposure within the mammalian brain remains unknown. We have recently found that the RNA binding protein, Rbm39, is upregulated in response to ethanol exposure in both the human and mouse embryonic cortex. Our preliminary data suggests that the upregulation of Rbm39 is required for protecting neural progenitor cells from both cell death and cell cycle arrest in embryonic mouse cortices exposed to ethanol. However, alterations in Rbm39 expression, whether due to loss- or gain-of- function, do not show obvious effects on normal cortical development. These results suggest that the Rbm39 plays specific roles resulting from ethanol exposure. In addition, we have found that the Rbm39 regulates the post-transcriptional modifications of specific mRNAs that are required for adaptive cellular protection from ethanol. Therefore, we hypothesize that the Rbm39 coordinates post-transcriptional modification through RNA- operons after exposure to ethanol, providing an immediate and adaptive system in protecting cells within the embryonic cortex. We will examine this hypothesis through three discrete aims. Aim 1 will define the requirement of Rbm39 for neural protection by knocking down Rbm39 in embryonic cortices exposed to ethanol. Aim 2 will determine whether exogenous increased of Rbm39 activity on RNA- operons can further reduce the brain damages by ethanol. Aim3 will examine whether Rbm39 orchestrates immediate post-transcriptional modification of specific genes in response to ethanol exposure.