Mechanisms of Reelin Action on neuronal Migration During Neocortical Lamination

Reelin 对新皮质层压期间神经元迁移的作用机制

• 批准号: 7915713
• 负责人: Santos Joe Franco
• 金额: $ 5.77万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915713
• 关键词: Address; Affect; Architecture; Autistic Disorder; Basement membrane; Behavior; Brain; Cell Surface Receptors; Cell physiology; Cells; Cerebral cortex; Clinical; Complex; Cortical Cell Layer; Data; Defect; Development; Development Polarity; Disease; Epilepsy; Fiber; Gene Transfer; Genetic; Genetic Recombination; Goals; Human; Image; Inherited; Knowledge; Mental Retardation; Methodology; Methods; Modeling; Molecular; Morphology; Mutant Strains Mice; Neocortex; Neuroglia; Neurologic; Neurons; Parents; Pathology; Pathway interactions; Positioning Attribute; Process; Radial; Reelin Signaling Pathway; Role; Schizophrenia; Signal Transduction; Signaling Molecule; Small Interfering RNA; Staging; Structure; Symptoms; Syndrome; Technology; Testing; Time; base; cell behavior; cell motility; cell type; in utero; insight; migration; neocortical; nervous system disorder; neuronal cell body; progenitor; receptor; reelin receptor; scaffold; tool

DESCRIPTION (provided by applicant): Disruption of the laminar architecture of the neocortex is associated with more than 25 human neurological disorders, including epilepsy, schizophrenia, autism and mental retardation. Cortical layers are established by the migration of neurons from proliferative zones into the developing cortical wall. Thus, knowledge of how neuronal migration is regulated is critical for elucidating the mechanisms by which layer formation is achieved, and will likely provide insights into the pathological changes associated with several neurological disorders. My long-term objective is to define the mechanisms that control development of the laminar structure of the cerebral cortex. As a first step, I propose here to study the mechanisms by which reelin controls the formation of cortical cell layers. The central hypothesis of my proposal is that reelin targets distinct cellular functions in RGCs and migrating neurons that ultimately control cortical lamination. To test this hypothesis, the following specific alms will be pursued: Aim 1: Determine the mechanisms by which reelin affects RGC behavior. The proposed methods for achieving this goal are: (i) develop based on CRE/LOX recombination, siRNA expression and in utero gene transfer to perturb reelin signaling in RGCs without affecting signaling to neurons, (ii) use real-time imaging to determine the cell-autonomous defects in RGC process outgrowth and attachment that result from inactivation of reelin signaling, (iii) determine the extent to which defects in RGCs secondarily affect migration of cortical neurons, (iv) target cell-surface receptors implicated in reelin signaling to determine their roles in RGC function. Aim 2: Determine the mechanism by which reelin controls the migratory behavior of cortical neurons. The proposed methods for achieving this goal are: (i) use strategies similar to those described in Aim 1 to selectively inactivate reelin signaling in migrating neurons and study effects on their behavior, such as motility, development of polarity and somal translocation, (ii) developed mutant mouse lines suitable for selective genetic perturbation of reelin signaling in early- or late-born neurons, (iii) test the extent to which inactivation of reelin signaling during different modes of migration affects cortical lamination. Relevance: Abnormal development of the cerebral cortex causes more than 25 different human neurological syndromes that are characterized by significant clinical symptoms, including epilepsy, autism, schizophrenia and mental retardation. Therefore, understanding how the cerebral cortex is formed during development of the brain is expected to provide important information on the pathology of these diseases.

描述（由申请人提供）：新皮层的层状结构的破坏与25多种人类神经系统疾病有关，包括癫痫，精神分裂症，自闭症和心理迟缓。皮质层是通过神经元从增殖区域迁移到发育中的皮质壁建立的。因此，了解如何调节神经元迁移对于阐明实现层形成的机制至关重要，并且可能会提供有关与多种神经系统疾病相关的病理变化的见解。我的长期目标是定义控制大脑皮层层状结构发展的机制。作为第一步，我在这里建议研究reelin控制皮质细胞层的形成的机制。我的建议的中心假设是，reelin靶向RGC中的不同细胞功能和最终控制皮质层压的神经元的迁移。为了检验这一假设，将追求以下特定施舍：目标1：确定reelin影响RGC行为的机制。 The proposed methods for achieving this goal are: (i) develop based on CRE/LOX recombination, siRNA expression and in utero gene transfer to perturb reelin signaling in RGCs without affecting signaling to neurons, (ii) use real-time imaging to determine the cell-autonomous defects in RGC process outgrowth and attachment that result from inactivation of reelin signaling, (iii) determine the extent to which RGC中的缺陷第二会影响皮质神经元的迁移，（IV）靶细胞表面受体与reelin信号传导有关，以确定其在RGC功能中的作用。目标2：确定reelin控制皮质神经元迁移行为的机制。 The proposed methods for achieving this goal are: (i) use strategies similar to those described in Aim 1 to selectively inactivate reelin signaling in migrating neurons and study effects on their behavior, such as motility, development of polarity and somal translocation, (ii) developed mutant mouse lines suitable for selective genetic perturbation of reelin signaling in early- or late-born neurons, (iii) test the extent to which inactivation of reelin不同迁移模式期间的信号会影响皮质层压。相关性：脑皮质的异常发育引起25种以上不同的人类神经系统综合征，其特征是具有重大临床症状的特征，包括癫痫，自闭症，精神分裂症和智力低下。因此，了解如何在大脑发育过程中形成大脑皮质，以提供有关这些疾病病理学的重要信息。