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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：
10330015
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10330015
关键词：
Adaptor Signaling Protein Affect Alleles Apical Biological Brain Diseases Cell Cycle Cell physiology Cells Cerebral cortex Cerebrum Characteristics Complex Cortical Column Cortical Malformation DNA Sequence Alteration Development Diagnostic Dissection Epilepsy Epithelial Equilibrium Generations Genes Genetic Genetic Models Glial Differentiation Goals Growth Human Image Instruction Label Lead Link Logic Mediator of activation protein Microcephaly Microgyria Microtubules Minus End of the Microtubule Molecular Molecular Probes Morphology Mosaicism Mus Mutation Neurodevelopmental Disorder Neuroglia Neurons Organization administrative structures Outcome Process Proteins Proteomics Radial Research Role Schizencephaly Schizophrenia Services Signal Transduction Surface Surveys Testing Therapeutic Thinness Ventricular Width Work autism spectrum disorder base brain abnormalities brain malformation cell motility glial cell development imaging approach insight lissencephaly malformation migration mouse genetics mutant neurogenesis neuronal cell body 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、平铺组织作为一个指导性的框架，在发育中的大脑中产生和组织神经元，皮层发育中的大脑皮层的这种基本细胞特征的破坏导致一系列神经发育障碍（例如，自闭症、精神分裂症和癫痫），脑畸形（例如，无脑畸形，无脑畸形，小脑畸形，和巨/微脑回）。然而，对放射状胶质细胞平铺的分子逻辑知之甚少，它是如何驱动大脑皮层的适当形成的。我们发现RGC平铺是 Memo 1（细胞运动调节因子1）。MEMO 1基因突变导致自闭症。 Memo 1因此提供了一个了解放射状胶质细胞平铺机制的窗口，大脑皮层的最终组装。利用祖细胞特异性 Memo 1小鼠遗传模型，基于MADM的放射状胶质细胞分化谱，定位 Memo 1相互作用组，Memo 1细胞功能的机械解剖， Memo 1缺陷型放射状胶质细胞功能及MEMO 1突变的功能分析自闭症先证者，我们的目标是（a）发现Memo 1在RGC平铺中的作用，结果形成大脑皮层，（B）鉴定有助于并确定RGC平铺，以及（c）询问MEMO 1对皮层的贡献，与自闭症有关的畸形总的来说，这项工作的结果将揭示放射状胶质细胞平铺的分子逻辑，这一过程对皮质神经元的重要相关性，发展，以及这个过程中的变化如何导致大脑畸形，神经发育障碍重要的是，了解放射状神经胶质细胞是如何组装的，并适当组织以促进大脑皮层的形成，重新制定皮质生成的规则，为更好的诊断和治疗见解服务神经发育障碍