Role of Radial Glial Tiling in the Formation and Malformation of the Cerebral Cortex

径向胶质平铺在大脑皮层形成和畸形中的作用

基本信息

批准号：
10549361
负责人：
EVA S ANTON
金额：
$ 50.86万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2019-05-08 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10549361
关键词：
Adaptor Signaling Protein Affect Alleles Apical Biological Brain Diseases Cell Cycle Cell physiology Cells Cerebral cortex Complex Cortical Column Cortical Malformation DNA Sequence Alteration Development Diagnostic Dissection Epilepsy Epithelium Equilibrium Generations Genes Genetic Genetic Models Glial Differentiation Goals Growth Human Image Label Lead Link Logic Maps Mediator Membrane Microcephaly Microgyria Microtubules Minus End of the Microtubule Molecular Molecular Probes Morphology Mus Mutation Neurodevelopmental Disorder Neuroglia Neurons Organization administrative structures Outcome Process Proliferating Proteins Proteomics Radial Research Role Schizencephaly Schizophrenia Services Signal Transduction Surface Surveys Testing Therapeutic Thinness Ventricular Visualization Width Work autism spectrum disorder brain abnormalities brain malformation cell assembly cell motility glial cell development imaging approach inducible Cre insight lissencephaly malformation migration mosaic mosaic analysis mouse genetics mutant neurogenesis neuronal cell body neuronal circuitry newborn neuron proband progenitor scaffold tool

项目摘要

Regularly interspaced, non-overlapping, tiled organization of polarized radial glial cells (RGCs) serves as an instructive framework to generate and organize neurons in the developing cerebral cortex. Disruptions in this fundamental cellular feature of the developing cerebral cortex lead to a spectrum of neurodevelopmental disorders (e.g., autism, schizophrenia, and epilepsy) and brain malformations (e.g., lissencephaly, schizencephaly, microencephaly, and macro/microgyria). However, little is known about the molecular logic of radial glial tiling and how it drives the appropriate formation of the cerebral cortex. We discovered that RGC tiling is dependent on Memo1 (Mediator of cell motility 1). Genetic mutations in MEMO1 lead to autism. Memo1 thus provides a window into the mechanisms that instruct radial glial tiling and the resultant assembly of the cerebral cortex. Leveraging the latest advances in progenitor specific mouse genetic models of Memo1, MADM based profiling of radial glial differentiation, mapping of Memo1 interactome, mechanistic dissection of cellular functions of Memo1, live imaging of Memo1 deficient radial glial cell functions, and functional analysis of MEMO1 mutation from autism probands, we aim to (a) discover the role of Memo1 in the tiling of RGCs and the resultant formation of the cerebral cortex, (b) identify the Memo1 interactome that contributes to and determines RGC tiling, and (c) interrogate the contributions of MEMO1 to cortical malformations associated with autism. Collectively, the outcome of this work will reveal the molecular logic underlying radial glial tiling, the vital relevance of this process for cortical development, and how changes in this process can cause brain malformations and neurodevelopmental disorders. Importantly, understanding how radial glial cells are assembled and organized appropriately to facilitate cerebral cortical formation offers the opportunity to redraw the rules of corticogenesis in the service of better diagnostic and therapeutic insights into neurodevelopmental disorders.

极化放射状胶质细胞 (RGC) 的规则间隔、非重叠、平铺组织作为在发育中的大脑中生成和组织神经元的指导框架皮质。发育中的大脑皮层的这一基本细胞特征的破坏会导致一系列神经发育障碍（例如自闭症、精神分裂症和癫痫症）以及脑畸形（例如无脑畸形、裂脑畸形、小脑畸形和宏观/小回旋）。然而，人们对放射状胶质平铺的分子逻辑知之甚少。它如何驱动大脑皮层的适当形成。我们发现 RGC 平铺是依赖于 Memo1（细胞运动中介 1）。 MEMO1 基因突变会导致自闭症。因此，Memo1 为了解指导径向胶质平铺和大脑皮层的最终组装。利用祖细胞特异性的最新进展基于 Memo1、MADM 的小鼠遗传模型的放射状胶质细胞分化分析、绘图 Memo1 相互作用组、Memo1 细胞功能的机械剖析、实时成像 Memo1 缺陷放射状胶质细胞功能以及 MEMO1 突变的功能分析对于自闭症先证者，我们的目标是 (a) 发现 Memo1 在 RGC 平铺和大脑皮层的最终形成，(b) 识别出有助于并确定 RGC 平铺，以及 (c) 询问 MEMO1 对皮质的贡献与自闭症相关的畸形。总的来说，这项工作的结果将揭示径向胶质平铺的分子逻辑，该过程与皮质的重要相关性发育，以及这个过程的变化如何导致大脑畸形和神经发育障碍。重要的是，了解放射状胶质细胞是如何组装的并适当组织以促进大脑皮层形成提供了机会重新制定皮质生成规则，以提供更好的诊断和治疗见解转化为神经发育障碍。