Molecular Mechanisms That Control Neuronal Positioning

控制神经元定位的分子机制

• 批准号: 6843259
• 负责人: Brian W. Howell
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6843259
• 关键词: binding proteins; brain; brain mapping; cell growth regulation; cell migration; cerebellum; cerebral cortex; developmental genetics; developmental neurobiology; gene expression; gene mutation; genetic regulation; hippocampus; laboratory mouse; nerve /myelin protein; neuroanatomy; neurogenesis; neurogenetics; neurons; phosphoproteins; phosphorylation; protein protein interaction; protein signal sequence; protein tyrosine kinase; tissue /cell culture

Genetic disorders that produce neuronal ectopias can result in the development of epilepsy or, in extreme cases, severe mental retardation. Our lab studies the molecular controls of neuronal migration with the goal of understanding the events that are required to orchestrate the appropriate formation and function of the nervous system. Understanding of the mechanisms regulating neuronal migration has been facilitated by studies on mouse mutants that have neuronal positioning defects. Analyses of the defective genes in these mice have led to insights about the mechanisms regulating neuronal migration. This lab focuses on the products of four genes that work together on a common signaling pathway to regulate neuronal placement. These proteins include the secreted protein, Reelin, that acts through the cell surface receptors ApoER2 and VLDLR to induce the tyrosine phosphorylation of a cytoplasmic protein Dab1. The Dab1 tyrosine phosphorylation sites that are regulated by this cascade have been shown genetically to be required for Dab1 function and normal brain development. We have therefore concentrated our efforts on identifying and characterizing proteins that interact with Dab1 in a tyrosine phosphorylation dependent manner. Recently, we have identified Nck beta as one such protein. In cultured fibroblasts, we have demonstrated that co-overexpression of Dab1 and Nck beta leads to alterations in the actin cytoskeleton. In response to Reelin stimulation, Nck beta translocates from the cell soma into cellular processes where it may act to regulate cytoskeletal dynamics. We are currently analyzing other Dab1 binding proteins to determine if they are regulated by Reelin signaling. The components of this pathway continue to be expressed in adult animals. Therefore, in addition to analyzing a role for this cascade in the formation of the brain, we are also investigating a role for this signaling cascade in the maintenance of nervous system function. This is being investigated using a conditional allele for Dab1, which shall be inactivated in a subset of neurons postnatally.

产生神经元异位的遗传性疾病可能导致癫痫的发生，或者在极端情况下，导致严重的精神发育迟缓。我们的实验室研究神经元迁移的分子控制，目的是了解协调神经系统的适当形成和功能所需的事件。通过对具有神经元定位缺陷的小鼠突变体的研究，促进了对调节神经元迁移的机制的理解。对这些小鼠中缺陷基因的分析使我们对调节神经元迁移的机制有了新的认识。该实验室专注于四个基因的产物，这些基因在共同的信号通路上共同作用以调节神经元的位置。这些蛋白质包括分泌蛋白质Reelin，其通过细胞表面受体ApoER 2和VLDLR起作用以诱导胞质蛋白质Dab 1的酪氨酸磷酸化。Dab1酪氨酸磷酸化位点，这是由这个级联调节已被证明是Dab1功能和正常的大脑发育所需的遗传。因此，我们集中我们的努力，确定和表征蛋白质的相互作用与Dab1的酪氨酸磷酸化依赖的方式。最近，我们已经确定Nck β是这样一种蛋白质。在培养的成纤维细胞中，我们已经证明了Dab1和Nck β的共同过表达导致肌动蛋白细胞骨架的改变。响应于Reelin刺激，Nck β从细胞索马易位到细胞过程中，在那里它可以起作用以调节细胞骨架动力学。我们目前正在分析其他Dab1结合蛋白，以确定它们是否受Reelin信号转导的调控。该途径的组分在成年动物中继续表达。因此，除了分析这种级联在大脑形成中的作用外，我们还研究了这种信号级联在维持神经系统功能中的作用。这是正在调查使用Dab1的条件等位基因，这将在出生后的神经元的子集失活。