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

基本信息

批准号：
9810128
负责人：
Mariah Lawler Hoye
金额：
$ 6.12万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9810128
关键词：
Ablation Alpha Granule Apoptosis Biological Assay Brain CRISPR/Cas technology Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Cell Line Cell Proliferation Regulation Cerebral cortex Clinical Clinical Data Clustered Regularly Interspaced Short Palindromic Repeats Cytoplasmic Granules Data Defect Development Disability phenotype Disease Dominant-Negative Mutation Electroporation Embryo Engineering Epilepsy Etiology Event Female Generations Genes Genetic Grant Human Impairment Intellectual functioning disability Label Lead Messenger RNA Metabolism Molecular Mus Mutation Nature Nerve Degeneration Neuronal Differentiation Neurons Pathologic Patients Phenotype Point Mutation Proteins RNA RNA Helicase RNA Processing Regulation Ribonucleoproteins Ribosomes Role Silver Stains Stem cells Testing Toxic effect Training Transcript Translation Initiation Translational Regulation Translations Work autism spectrum disorder base brain malformation cell type deep sequencing excitatory neuron in utero in vivo induced pluripotent stem cell insight live cell imaging loss of function loss of function mutation migration mouse model mutant nerve stem cell nervous system disorder neuroregulation progenitor recruit

项目摘要

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 in neural cells induces ribonucleoprotein (RNP) granules, which are RNA-protein assemblies 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 that DDX3X-ID mutants impair RNP interactions. 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 identify key DDX3X translational targets relevant for progenitor proliferation. Aim 3 characterizes 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 RNA regulation required for normal brain development and the mechanism by which aberrations can lead to ID.

RNA解旋酶DDX3X中的突变与多种发育缺陷和大脑有关畸形和占女性智力残疾（ID）病例的1-3％。有趣的是，表达神经细胞中的DDX3X突变体诱导核糖核蛋白（RNP）颗粒，它们是RNA蛋白质组件与神经疾病有关。我们的初步数据表明DDX3X调节神经祖细胞增殖及其形成神经元的倾向。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控制神经的假设祖细胞增殖和命运决定通过调节和DDX3X-ID突变体损害RNP相互作用。 AIM 1使用鼠标模型来定义DDX3X耗竭的明显后果皮质发育过程中的祖细胞和神经元。 AIM 2采用基于翻译的测定来识别密钥 DDX3X转化目标与祖细胞增殖有关。 AIM 3表征了DDX3X-ID的性质突变颗粒和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脑发育所需的RNA调控的理解以及通过畸变可能导致ID。