Coordination of projection neuron fate and position by let-7

let-7 协调投射神经元的命运和位置

• 批准号: 10722629
• 负责人: Anna La Torre
• 金额: $ 42.24万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722629
• 关键词: Affect; Apical; Behavior; Biological; Biosensor; Cell Cycle; Cells; Central Nervous System; Cognition Disorders; Competence; Conserved Sequence; Core Protein; Data; Date of birth; Defect; Development; Developmental Biology; Embryonic Development; Environment; Failure; Image; Imaging Techniques; Knowledge; Lead; Link; Location; Mass Spectrum Analysis; MicroRNAs; Modeling; Molecular; Molecular Mechanisms of Action; Neocortex; Neuroglia; Neurologic; Neurons; Pattern; Population; Population Projection; Positioning Attribute; Process; Psyche structure; Radial; Research; Role; Side; Signal Transduction; Surface; Testing; Transplantation; brain malformation; cell type; cohort; lateral ventricle; member; migration; multipotent cell; neocortical; nerve stem cell; neural; neurogenesis; novel; overexpression; postmitotic; progenitor; response; ubiquitin-protein ligase

Project Summary: The central nervous system contains a myriad of different cell types that receive and integrate information from the environment to generate the appropriate biological responses. Failure to produce the right composition of neuronal subtypes or defects in their localization can result in several mental and physical conditions that range from cognitive disorders to severe brain malformations. In the neocortex, a specialized pool of multipotent cells -called radial glial cells- gives rise to all the different populations of projection neurons in a conserved sequence. Importantly, early born projections neurons localize at the apical side of the cortical plate whereas later born neurons localize atop of their predecessors. Despite the strong correlation between projection neuron fate identity and position, the molecular mechanisms involved in such correlation remain elusive. MicroRNAs (miRNAs) have recently been uncovered as strong cell fate determinants and we and others have shown that let-7 expression in radial glia cells promotes the neurogenesis of late born cortical projection neurons. Importantly, we further demonstrate that let-7 expression positive correlates with projection neuron location in upper cortical layers (i.e., closer to the pial surface). Our preliminary data show that let-7 regulates neuron migration by opposing the expression of Rbx2, a core member of the E3 ubiquitin ligase CRL5, previously identified as a key factor to end projection neuron migration. Thus, we hypothesize that elevated expression of let-7 in late-born projection neurons reduces the activity of CRL5, promoting neuron migration. The proposed research will identify let-7 as the first coordinator of neural progenitor competence and projection neuron migration/localization, and unveil its molecular mechanism of action.

项目摘要： 中枢神经系统包含无数不同的细胞类型，这些细胞类型接收并整合了来自 产生适当生物学反应的环境。未能产生正确的组成 神经元亚型或其本地化缺陷可能导致几种范围的精神和身体状况 从认知障碍到严重的大脑畸形。在新皮层中，一个专门的多元细胞池 称为径向神经胶质细胞 - 在保守的序列中产生所有不同投影神经元种群。 重要的是，早期出生的预测神经元位于皮质板的顶端一侧，而后来出生 神经元位于其前辈的顶部。尽管投射神经元命运之间有很强的相关性 身份和位置，涉及这种相关性的分子机制仍然难以捉摸。 microRNA （miRNA）最近被发现为强大的细胞命运决定因素，我们和其他人表明 radial胶质细胞中的Let-7表达促进了晚期皮质投射神经元的神经发生。 重要的是，我们进一步证明了let-7表达阳性与投影神经元的位置相关 上皮层（即，靠近皮尔表面）。我们的初步数据表明，Let-7调节神经元 通过反对E3泛素连接酶CRL5的核心成员RBX2的表达来迁移 被确定为结束投射神经元迁移的关键因素。因此，我们假设 Let-7在后期的投射神经元中降低了CRL5的活性，从而促进了神经元迁移。提议 研究将确定Let-7是神经祖细胞能力和投射神经元的第一个协调员 迁移/定位，并揭示其分子作用机理。