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: 7752140
• 负责人: Santos Joe Franco
• 金额: $ 5.53万
• 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/7752140
• 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）：新皮层层状结构的破坏与超过25种人类神经系统疾病相关，包括癫痫、精神分裂症、自闭症和精神发育迟滞。皮质层是通过神经元从增殖区迁移到发育中的皮质壁而建立的。因此，了解神经元迁移是如何调节的是至关重要的阐明层形成的机制，并可能提供与几种神经系统疾病相关的病理变化的见解。我的长期目标是确定控制大脑皮层层状结构发育的机制。作为第一步，我建议在这里研究的机制，其中reelin控制皮层细胞层的形成。我的建议的中心假设是，reelin的目标是在RGCs和迁移神经元，最终控制皮层分层不同的细胞功能。为了检验这一假设，以下具体施舍将追求：目的1：确定的机制，其中reelin影响RGC的行为。实现这一目标的拟议方法是：（i）基于CRE/LOX重组、siRNA表达和子宫内基因转移开发以干扰RGC中的reelin信号传导而不影响对神经元的信号传导，（ii）使用实时成像来确定RGC过程生长和附着中的细胞自主缺陷，其由reelin信号传导的失活引起，（iii）确定RGC缺陷继发影响皮质神经元迁移的程度。（iv）涉及reelin信号传导的靶细胞表面受体，以确定它们在RGC功能中的作用。目的2：确定reelin控制皮层神经元迁移行为的机制。实现这一目标的拟议方法是：（i）使用类似于目标1中所述的策略来选择性地干扰迁移神经元中的reelin信号传导，并研究对它们的行为的影响，例如运动性、极性发育和染色体易位，（ii）开发适合于在早生或晚生神经元中选择性遗传干扰reelin信号传导的突变小鼠品系，（iii）测试在不同的迁移模式期间reelin信号传导的失活影响皮质层压的程度。相关性：大脑皮层的异常发育导致超过25种不同的人类神经系统综合征，其特征在于显著的临床症状，包括癫痫、自闭症、精神分裂症和精神发育迟滞。因此，了解大脑皮层在大脑发育过程中是如何形成的，有望为这些疾病的病理学提供重要信息。