The role of an Intellectual Disability gene, DDX3X, in neural progenitors during brain development

智力障碍基因 DDX3X 在大脑发育过程中神经祖细胞中的作用

• 批准号: 10395855
• 负责人: Mariah Lawler Hoye
• 金额: $ 3.3万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-05-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395855
• 关键词: role; Intellectual; Disability; gene; DDX3X

Abstract: Mutations in the RNA helicase DDX3X are associated with a wide range of developmental deficits and brain malformations and account for 1-3% of Intellectual disability (ID) cases in females. Interestingly, expression of DDX3X mutants induces stress granule-like complexes, an RNA-protein assembly associated with neurological diseases. Our preliminary data indicate DDX3X regulates neural progenitor proliferation and their propensity to form neurons. However, the distinct requirements for DDX3X in neural progenitors and neurons have not been characterized nor the mechanisms by which ID-associated DDX3X mutations impair cortical development. Here, we test the hypothesis that DDX3X controls neural progenitor proliferation and fate decisions through regulation of translation and SG dynamics. Aim 1 uses mouse models to define the distinct consequences of Ddx3x depletion in progenitors and neurons during cortical development. Aim 2 employs translation-based assays to understand how DDX3X translational control impacts progenitor proliferation. Aim 3 seeks to characterize the nature of DDX3X ID-mutant granules and the protein interactome of WT DDX3X and ID-mutants. Upon completion, this proposal will enhance our understanding of post-transcriptional RNA regulation required for normal brain development and the mechanism by which aberrations can lead to ID.

抽象的： RNA解旋酶DDX3X中的突变与多种发育缺陷有关 脑畸形，占女性智力残疾（ID）病例的1-3％。有趣的是， DDX3X突变体的表达诱导应力颗粒状复合物，RNA-蛋白质组装相关 神经疾病。我们的初步数据表明DDX3X调节神经祖细胞增殖 以及它们形成神经元的倾向。但是，神经中DDX3X的独特要求 祖细胞和神经元尚未表征，也没有ID相关的机制 DDX3X突变会损害皮质发育。在这里，我们检验了DDX3X控制的假设 通过调节翻译和SG，神经祖细胞增殖和命运决定 动力学。 AIM 1使用鼠标模型来定义祖细胞中DDX3X耗竭的明显后果 和皮质发育过程中的神经元。 AIM 2使用基于翻译的测定法来了解如何 DDX3X翻译控制会影响祖细胞增殖。 AIM 3试图表征 DDX3X ID突变颗粒和WT DDX3X和ID-突变体的蛋白质相互作用。完成后， 该建议将增强我们对正常文字后RNA调节的理解 大脑发育和畸变可能导致ID的机制。