Doublecortin in Neuronal Migration

双皮质素在神经元迁移中的作用

基本信息

批准号：
7788001
负责人：
JOSEPH G GLEESON
金额：
$ 25.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-06-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7788001
关键词：
Address Brain C-terminal Cells Centrosome Cerebral Palsy Clinical Complementary DNA Cortical Malformation Coupling Defect Development Electroporation Epilepsy Event Family Female Gene Family Genes Genetic Goals Homologous Gene Human Immigration In Vitro Knock-in Mouse Knock-out Lead Life Link Mediating Mediation Mental Retardation Methods Microtubule-Associated Proteins Microtubules Miller-Dieker Syndrome Molecular Movement Mus Mutate Mutation N-terminal Neurites Neurocognitive Deficit Neuronal Migration Disorder Neurons Nuclear Patients Phase Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physical condensation Play Point Mutation Process Protein Dephosphorylation Proteins Regulation Role Seizures Serine Signal Pathway Signal Transduction Syndrome Testing Threonine Travel Work Wrist adapter protein adult stem cell base cell motility cellular imaging human disease in utero in vivo infancy knock-down lissencephaly male migration mouse model neocortical neuron development neuronal cell body public health relevance relating to nervous system research study spinophilin

项目摘要

DESCRIPTION (provided by applicant): Malformations of cortical development due to disorder of neuronal migration are increasingly recognized as a common cause of epilepsy, mental retardation, and cerebral palsy. The doublecortin (DCX) gene is critical for neuronal migration in humans, as mutations result in X- linked lissencephaly in males and double cortex in females, producing severe neurocognitive deficits. We identified the DCX gene and found mutations in patients with this condition. We identified its role as a microtubule-associated protein (MAP) and its involvement in critical signaling pathways through phosphorylation- and dephosphorylation-dependent mechanisms. We uncovered important cellular roles for Dcx in cells, including mediation of nuclear-centrosome coupling, organization of microtubule condensation at the neurite "wrist" and a requirement in adult stem cell migration. Dcx is part of a gene family also containing Dclk1 and Dclk2, each encoding a strongly brain-expressed protein with a closely matching Dcx domain and kinase domain. We found that Dcx;Dclk1 knockouts displays severe cortical neuronal migration defects that mirror lissencephaly, whereas Dcx;Dclk2 knockouts displays severe seizures, also part of the clinical picture of lissencephaly. However, the role of the kinase activities in neuronal development are unknown. The overall goal of this renewal application is to elucidate the signaling mechanisms of the Dcx gene family in neuronal development and brain function. We will utilize knockout and knock-in and genetic rescue experiments in mice combined with advanced live-cell imaging capabilities and in vivo analysis that will synergize to provide a powerful approach to address these goals. PUBLIC HEALTH RELEVANCE: The doublecortin gene family plays critical roles in brain development, resulting in severe forms of epilepsy and mental retardation when mutated. We will study the signaling mechanisms of the doublecortin gene family, in order to understand the basis of these human diseases.

描述（由申请人提供）：由于神经元迁移障碍而导致的皮质发育的畸形越来越被认为是癫痫，智力低下和脑瘫的常见原因。 Doublecortin（DCX）基因对于人类的神经元迁移至关重要，因为突变导致雄性X连接的Lissencephaly和女性的双层皮质，从而产生严重的神经认知缺陷。我们鉴定了DCX基因，并在患有这种情况的患者中发现了突变。我们确定了它作为微管相关蛋白（MAP）的作用及其通过磷酸化和去磷酸化依赖性机制的临界信号通路的参与。我们发现了DCX在细胞中的重要细胞作用，包括核中心体偶联的介导，在神经突的“腕部”中的微管凝结组织以及成人干细胞迁移的要求。 DCX是一个含有DCLK1和DCLK2的基因家族的一部分，每个基因家族都编码具有紧密匹配的DCX结构域和激酶结构域的强烈脑表达的蛋白质。我们发现DCX; DCLK1敲除显示了镜像Lissphaly的严重皮质神经元迁移缺陷，而DCX； DCLK2敲除显示严重的癫痫发作，这也是Lissencephaly的临床图片的一部分。但是，激酶活性在神经元发育中的作用尚不清楚。这种更新应用的总体目标是阐明DCX基因家族在神经元发育和脑功能中的信号传导机制。我们将利用小鼠中的敲除和敲除和遗传救援实验，结合先进的活细胞成像能力和体内分析，这些分析将协同作用，以提供有力的方法来解决这些目标。公共卫生相关性：DoubleCortin基因家族在大脑发育中起着关键作用，导致突变时严重形式的癫痫和智力低下。我们将研究DoubleCortin基因家族的信号传导机制，以了解这些人类疾病的基础。