Role of CLASP2 in Neurodevelopment

CLASP2 在神经发育中的作用

• 批准号: 8776727
• 负责人: ANGELA HO
• 金额: $ 20.46万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776727
• 关键词: Actins; Adaptor Signaling Protein; Affect; Axon; Binding; Biochemical; Brain; Child; Childhood; Cognition; Cognitive deficits; Complex; Cytoskeletal Modeling; Cytoskeletal Proteins; Cytoskeleton; Data; Defect; Development; Diagnosis; Electroporation; Elements; Epilepsy; Extracellular Matrix Proteins; Genes; Genetic study; Glycoproteins; Goals; Golgi Apparatus; Health; 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; research study; response; small hairpin RNA; synaptogenesis

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：神经元迁移中断会导致严重的神经和发育障碍，例如认知缺陷和癫痫，这主要在儿科人群中出现。对于神经元正常迁移和大脑发育至关重要的信号通路是由进化上保守的糖蛋白 Reelin 启动的。 Reelin 通路中的人类突变产生的表型类似于细胞骨架蛋白突变所诱导的表型，这些突变破坏了微管和肌动蛋白的功能。这些儿童遗传学研究的结果强烈表明，包括 Reelin 通路在内的多种信号通路汇聚于下游细胞骨架蛋白，从而影响正常的神经元迁移、大脑发育和认知。我们使用系统生物学方法来鉴定微管稳定 CLASP2 作为 Reelin 信号传导的关键细胞骨架修饰剂。我们之前发现CLASP2在体外神经元发育过程中调节几个重要的表型，包括高尔基体形态、神经元分支、轴突规范和突触活性，这些表型也受到Reelin信号的调节。然而，人们对 CLASP2 的作用及其与发育中大脑中 Reelin 信号通路的关联知之甚少。因此，我们的目标是了解 Reelin 信号如何在神经元和大脑发育过程中调节 CLASP2 介导的细胞骨架功能。第一个目标是定义 CLASP2 与 Reelin 通路下游节点 Dab1 的相互作用，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。拟议的研究旨在加深对 Reelin 如何通过细胞骨架重组（正常大脑发育的关键要素）控制神经元迁移的理解。

项目成果

CLASP2 Links Reelin to the Cytoskeleton during Neocortical Development.

• DOI: 10.1016/j.neuron.2017.02.039
• 发表时间: 2017-03-22
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Dillon GM;Tyler WA;Omuro KC;Kambouris J;Tyminski C;Henry S;Haydar TF;Beffert U;Ho A
• 通讯作者: Ho A