Non-coding RNA regulation of early neural development

早期神经发育的非编码RNA调控

• 批准号: 10318617
• 负责人: Lee A. Niswander
• 金额: $ 55.18万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318617
• 关键词: ATRX gene; Address; Animal Model; Attention; Biogenesis; Biology; Brain; Brain Diseases; Bruck-de Lange syndrome; CRISPR/Cas technology; CSPG6 gene; Cell Differentiation process; Cell Line; Chromosome Cohesion; Chromosome Deletion; Chromosome Segregation; Complex; Congenital Abnormality; Data; Defect; Deletion Mutation; Development; Developmental Process; Embryo; Ensure; Equilibrium; Exons; Functional disorder; Gene Mutation; Genes; Genetic; Goals; Growth; Human; In Vitro; Instruction; Knock-out; Knowledge; Lead; Link; Macrocephaly; Maintenance; Mediating; Methyl-CpG-Binding Protein 2; MicroRNAs; Microcephaly; Mitosis; Mitotic; Modeling; Molecular; Multiprotein Complexes; Mus; Mutate; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuroepithelial; Neuronal Differentiation; Neuronal Injury; Neurons; Patients; Pattern; Phenotype; Plant Roots; Play; Polyadenylation; Process; Protein Isoforms; Proteins; RNA; Regulation; Rett Syndrome; Role; Sister Chromatid; Spinal Cord; Testing; Transcript; Untranslated RNA; cell behavior; cell type; cohesin; cohesion; gene function; in vivo; knock-down; mouse model; nerve stem cell; nervous system disorder; neurodevelopment; neuroregulation; novel; prevent; progenitor; scaffold; self-renewal; stem cell differentiation; stem cell proliferation; stem cells

Defects in neuroepithelial progenitor self-renewal and differentiation can result in profound neurodevelopmental disorders including devastating birth defects such as microcephaly. The long-term objective of the proposed studies is to understand how neuroepithelial progenitor cell self-renewal and differentiation are coordinated. This proposal specifically focuses on a long non-coding RNA (lncRNA) that is expressed early in mouse neuroepithelial progenitor cells and, as differentiation proceeds, the lncRNA transcript is processed to yield a microRNA that is involved in neuronal differentiation. Moreover, the lncRNA physically interacts with key microcephaly proteins but the functional relationship between the lncRNA and these proteins is unknown. The major questions addressed in three Aims are as follows. Aim 1 will test the hypothesis that the lncRNA functions - independent of the miRNA - in regulating neuroepithelial progenitor proliferation and survival. Aim 1 creates cell lines and mouse models with specific deletion mutations, including a small deletion of this locus observed in a patient with microcephaly, for functional studies. Aim 2 will explore the cellular mechanism underlying the microcephaly phenotype, preliminary data which suggests a mitotic arrest. Moreover, Aim 2 will address the hypothesis that the lncRNA functions as a scaffold to help maintain sister chromatid cohesion through its interactions with the Cohesin complex, which is also implicated in microcephaly. Aim 3 will explore the mechanism underlying the temporal-spatial difference between the lncRNA host transcript and the embedded miRNA. Our overall goal is to discover new mechanisms that coordinate neuroepithelial progenitor cell proliferation and differentiation, as well as to decipher how this unexplored lncRNA mechanistically acts to allow normal brain growth. Harnessing the potential of neuroepithelial progenitor cells holds promise for the treatment of neuronal injury and neurodegenerative diseases, and dysfunction of neuroepithelial progenitors is at the root of numerous neurological disorders. Our studies will provide mechanistic links between a novel lncRNA and known microcephaly proteins to greatly extend our knowledge of this profound brain disorder.

神经上皮祖细胞自我更新和分化的缺陷可导致严重的神经发育障碍。 包括毁灭性的出生缺陷如小头畸形在内的疾病。拟议的长期目标 研究的目的是了解神经上皮祖细胞的自我更新和分化是如何协调的。这 一项提案特别关注一种在小鼠早期表达的长非编码RNA（lncRNA）， 神经上皮祖细胞，并且随着分化的进行，lncRNA转录物被加工以产生 参与神经元分化的microRNA。此外，lncRNA与关键的 但是lncRNA和这些蛋白质之间的功能关系是未知的。的 三个目标所涉及的主要问题如下。目的1将测试lncRNA功能的假设， - 独立于miRNA -调节神经上皮祖细胞增殖和存活。目标1创建 具有特定缺失突变的细胞系和小鼠模型，包括在 一名患有小头畸形的患者，进行功能研究。目的2将探讨细胞机制的基础上， 小头畸形表型，初步数据表明有丝分裂阻滞。此外，目标2将解决 假设lncRNA作为一个支架，以帮助维持姐妹染色单体的凝聚力，通过其 与内聚蛋白复合物的相互作用，这也与小头畸形有关。目标3将探讨 lncRNA宿主转录物和嵌入的 小RNA。我们的总体目标是发现新的机制，协调神经上皮祖细胞 增殖和分化，以及破译这种未探索的lncRNA如何机械地发挥作用， 正常的大脑发育。利用神经上皮祖细胞的潜力为治疗带来了希望 神经元损伤和神经退行性疾病，神经上皮祖细胞功能障碍是根源 多种神经系统疾病我们的研究将提供一种新的lncRNA和 已知的小头畸形蛋白，以极大地扩展我们对这种深刻的大脑疾病的知识。