权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of CLASP2 in Neurodevelopment

CLASP2 在神经发育中的作用

基本信息

批准号：
8638557
负责人：
ANGELA HO
金额：
$ 24.56万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638557
关键词：
Actins Adaptor Signaling Protein Affect Axon Binding Biochemical Brain Child Childhood Cognition Cognitive deficits Complex Cytoskeletal Modeling Cytoskeletal Proteins Cytoskeleton DNA Sequence Rearrangement Data Defect Development Diagnosis Electroporation Elements Epilepsy Extracellular Matrix Proteins Genes Genetic Glycoproteins Goals Golgi Apparatus Human Immigration Impairment In Vitro Indium Induced Mutation Lead Learning Disabilities Link Lipoprotein Receptor Location Mediating Microtubules Molecular Morphogenesis Morphology Movement Mus Mutation Neurologic Neurons Pathway interactions Phenotype Phosphorylation Play Population Positioning Attribute Process Proteins Recruitment Activity Reelin Signaling Pathway Research Role Signal Pathway Signal Transduction Signaling Molecule Synapses Systems Analysis Systems Biology Transfection Tyrosine Phosphorylation Work apolipoprotein E receptor 2 axon guidance base extracellular in utero in vivo insight migration mutant neurodevelopment neuron development novel overexpression programs public health relevance research study response small hairpin RNA synaptogenesis

项目摘要

PROJECT SUMMARY: Disruption in neuronal migration results in severe neurological and developmental impairments such as cognitive deficits and epilepsy that are recognized primarily in the pediatric population. A signaling pathway crucial for proper neuronal migration and brain development is initiated by the evolutionarily conserved glycoprotein Reelin. Human mutations in the Reelin pathway generate phenotypes that mimic those induced by mutations in cytoskeletal proteins that disrupt the function of microtubules and actin. The culmination of these genetic studies in children strongly suggests that several signaling pathways including the Reelin pathway converge on downstream cytoskeletal proteins to affect proper neuronal migration, brain development and cognition. We used a systems biology approach to identify the microtubule-stabilizing CLASP2 as a key cytoskeletal modifier of Reelin signaling. We previously found that CLASP2 regulates several important phenotypes during neuronal development in vitro including Golgi morphology, neuronal branching, axon specification and synaptic activity, phenotypes that are also regulated by Reelin signaling. However, little is known about the role of CLASP2 and its association with the Reelin signaling pathway in the developing brain. Therefore, our goal is to understand how Reelin signaling regulates CLASP2-mediated cytoskeletal function during neuronal and brain development. In the first aim, we will define the interaction of CLASP2 with Dab1, a downstream node in the Reelin pathway, and then determine the functional consequences of this interaction. In the second aim, we will define the in vivo function of CLASP2 during brain development. The proposed studies aim to advance the understanding of how Reelin controls neuronal migration through cytoskeleton reorganization, key elements of normal brain development.

项目概要：神经元迁移的中断导致严重的神经和发育障碍，例如主要在儿科人群中发现的认知缺陷和癫痫。信号传导途径神经元迁移和大脑发育的关键是由进化上保守的糖蛋白Reelin。人在Reelin途径中的突变产生的表型模拟了破坏微管和肌动蛋白功能的细胞骨架蛋白突变。这些的高潮对儿童的遗传学研究强烈表明，包括Reelin通路在内的几种信号通路聚集在下游细胞骨架蛋白上，以影响适当的神经元迁移、大脑发育和认知.我们使用系统生物学方法来确定微管稳定CLASP2作为关键 Reelin信号传导的细胞骨架修饰剂。我们以前发现CLASP2调节几个重要的体外神经元发育过程中的表型，包括高尔基体形态、神经元分支、轴突这些表型也由Reelin信号传导调节。然而，已知CLASP2的作用及其与发育中大脑中的Reelin信号通路的关联。因此，我们的目标是了解Reelin信号如何调节CLASP2介导的细胞骨架功能在神经元和大脑发育过程中。在第一个目标中，我们将定义CLASP 2与Dab 1的相互作用，下游节点的Reelin途径，然后确定这种相互作用的功能后果。在第二个目标中，我们将定义CLASP2在大脑发育过程中的体内功能。拟议这些研究旨在进一步了解Reelin如何通过细胞骨架控制神经元迁移重组，正常大脑发育的关键要素。