Cellular and Molecular Mechanisms in Periventricular Heterotopia

脑室周围异位的细胞和分子机制

• 批准号: 8269069
• 负责人: VOLNEY L SHEEN
• 金额: $ 29.16万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269069
• 关键词: ADP-Ribosylation Factors; Accounting; Actin-Binding Protein; Actins; Address; Adherens Junction; Affect; Apical; Autopsy; Binding; Binding Sites; Brain; Brain Diseases; Brefeldin A; Bromodeoxyuridine; Capsid Proteins; Cell Adhesion; Cell Cycle; Cell Death; Cells; Cerebral cortex; Cerebrum; Coated vesicle; Collection; Cortical Malformation; Cyclic AMP-Dependent Protein Kinases; Cytoskeleton; Data; Defect; Development; Developmental Delay Disorders; Disease; Epilepsy; Epithelium; Exhibits; Failure; Functional disorder; Gait; Gene Mutation; Genes; Goals; Growth; Guanine; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Health; Human; Human Identifications; Humulus; Hydrocephalus; Immigration; Impairment; Lateral; Lead; Length; Link; Location; Mediating; Membrane; Mental Retardation; Microcephaly; Microfilaments; Molecular; Morphology; Mus; Mutate; Mutation; Neuroepithelial Cells; Neurons; Nodule; Pathway interactions; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Proteins; Regulation; Role; SNAP receptor; Sampling; Scaffolding Protein; Signal Transduction; Signaling Molecule; Testing; Therapeutic Intervention; Transport Vesicles; Ventricular; Vesicle; alpha-SNAP; brain malformation; cell motility; extracellular; filamin; gene function; lateral ventricle; malformation; migration; mouse model; mutant; nerve stem cell; nervous system disorder; neurodevelopment; neuroepithelium; periventricular heterotopia; positional cloning; progenitor; receptor binding; relating to nervous system; soluble NSF attachment protein; trafficking

DESCRIPTION (provided by applicant): Developmental failures in neuronal migration in the cerebral cortex result in epilepsy and mental retardation. Moreover, disorders in neural development account for a broad set of neurological diseases. Positional cloning has led to the identification of human genes mutated in periventricular heterotopia (PH), a malformation of cortical development characterized by the failure of a subset of neurons to migrate from the ventricle during cerebral cortical development. Mutations in either of two genes, the actin-binding filamin A (FLNA) and the vesicle transport related ARFGEF2, leads to severe defects in the initial migration of neurons along the ventricular lining and produces nearly identical radiographic findings of PH in humans. Mutations in the Napa gene in mice also lead to heterotopic nodules strikingly similar to those seen in humans. The central hypothesis of this application is that these common mutant phenotypes result from direct interactions between the encoded proteins or from a shared common pathway. The proposed functions of FLNA and ARFGEF2 appear quite disparate with FLNA implicated in neuronal motility due to its interactions with the actin cytoskeleton and BIG2 (encoded by ARFGEF2) involved in vesicle trafficking through its guanine exchange regulation of the ADP-ribosylation factors (ARFs). ARF activation is required during the assembly of protein coats for vesicle budding. Alpha-SNAP (encoded by Napa) is a NSF attachment protein, involved in SNAP receptor-mediated vesicle fusion. Collectively, however, all of these genes are involved in endosomal vesicle trafficking, either through regulation of actin filaments needed for transport, assembly of the coat protein, or fusion of the vesicle to the membrane. Thus, the role of FLNA and ARFGEF2 in giving rise to PH may share a common pathogenic mechanism with Napa by control over endosomal vesicle transport. Therefore the Specific Aims of this proposal are to determine: 1) which cellular defects seen following loss of FLNA function in mice contribute to PH formation, 2) whether FLNA binds BIG2 and directs BIG2 localization and BIG2-dependent ARF activation, and 3) whether loss of Napa or ARFGEF2 function in neural progenitors alters apical and/or basal adherens junctions leading to PH formation. PUBLIC HEALTH RELEVANCE: Human mutations in several genes are known to cause nearly identical brain malformations and result in epilepsy and mental retardation. The current proposal seeks to understand the cellular and molecular mechanisms of these genes, and how their function might be interrelated given their shared phenotype. Understanding the pathophysiology of human brain disorders provides a means for the development of therapeutic interventions.

描述（由申请人提供）：大脑皮层神经元迁移的发育障碍导致癫痫和智力障碍。此外，神经发育障碍是多种神经系统疾病的原因。位置克隆导致人类基因在脑室周围异位（PH）中突变，这是一种皮质发育畸形，其特征是在大脑皮质发育过程中部分神经元无法从心室迁移。肌动蛋白结合纤丝蛋白 A (FLNA) 和囊泡运输相关的 ARFGEF2 这两个基因中的任何一个的突变都会导致神经元沿着心室壁的初始迁移出现严重缺陷，并产生与人类几乎相同的 PH 放射学结果。小鼠纳帕基因的突变也会导致异位结节与人类中所见的异位结节惊人地相似。该应用的中心假设是这些常见的突变表型是由编码蛋白之间的直接相互作用或共享的共同途径引起的。 FLNA和ARFGEF2的拟议功能似乎与涉及神经元运动的FLNA完全不同，因为FLNA与肌动蛋白细胞骨架和BIG2（由ARFGEF2编码）相互作用，通过其对ADP-核糖基化因子（ARF）的鸟嘌呤交换调节参与囊泡运输。在囊泡出芽的蛋白质外壳组装过程中需要 ARF 激活。 Alpha-SNAP（由 Napa 编码）是一种 NSF 附着蛋白，参与 SNAP 受体介导的囊泡融合。然而，总的来说，所有这些基因都参与内体囊泡运输，或者通过调节运输所需的肌动蛋白丝、外壳蛋白的组装或囊泡与膜的融合。因此，FLNA和ARFGEF2在引起PH中的作用可能与Napa通过控制内体囊泡运输具有共同的致病机制。因此，该提案的具体目标是确定：1​​) 小鼠 FLNA 功能丧失后出现的哪些细胞缺陷有助于 PH 形成，2) FLNA 是否结合 BIG2 并指导 BIG2 定位和 BIG2 依赖性 ARF 激活，3) 神经祖细胞中 Napa 或 ARFGEF2 功能的丧失是否会改变顶端和/或基底粘附连接，导致 PH 形成。公共健康相关性：已知人类多个基因的突变会导致几乎相同的大脑畸形，并导致癫痫和智力低下。目前的提案旨在了解这些基因的细胞和分子机制，以及鉴于它们共有的表型，它们的功能如何相互关联。了解人类大脑疾病的病理生理学为开发治疗干预措施提供了一种手段。