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:7387309
- 负责人:
- 金额:$ 33.75万
- 依托单位:
- 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 2010-02-28
- 项目状态:已结题
- 来源:
- 关键词:Actin-Binding ProteinActinsAddressBiochemical GeneticsBrainCell NucleusCellsCentrosomeCerebral PalsyConditionCortical MalformationCouplingCyclin-Dependent Kinase 5CytoskeletonDataDefectDevelopmentDisruptionEpilepsyFamilyFemaleGene FamilyGene SilencingGenerationsGenesGoalsGrowth ConesHomologous GeneHumanImaging TechniquesImmigrationKnock-outKnockout MiceLeadLifeLinkMasksMediatingMental RetardationMicrotubule StabilizationMicrotubule-Associated ProteinsMicrotubulesMiller-Dieker SyndromeMolecularMovementMusMutationNeurocognitive DeficitNeuronal Migration DisorderNeuronsNuclearNuclear TranslocationPathway interactionsPatientsPhasePhenotypePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPhysical condensationPlacementProcessProtein DephosphorylationProtein phosphataseProteinsReagentRegulationReporterReportingRoleSignal PathwaySiteSmall Interfering RNASpecificitySyndromeTestingTransgenic OrganismsWorkcellular imagingin vivolink proteinmalemigrationnervous system disorderneuronal cell bodyneuronal growthnovelrelating to nervous systemspinophilin
项目摘要
Malformations of cortical development due to disorders of neuronal migration are increasingly recognized as a common
cause of epilepsy, mental retardation and cerebral palsy. The doublecortin (OCX) gene is critical for neuronal
migration in humans, as mutations result in X-linked lissencephaly in males and subcortical band heterotopia in
females, producing severe neurocognitive deficits. We identified the OCX gene, and found mutations in patients with
this condition. We identified its role as a microtubule (MT)-associated protein and its involvement in several signaling
pathways through phosphorylation-dependent mechanisms. We also identified a potential role for Dcx in coupling the
nucleus to the centrosome in a microtubule-dependent fashion during the nuclear translocation phase of migration. Dcx
is part of a gene family also containing Dckl and Dck2, each encoding a strongly brain-expressed protein with a closely
matching Dcx domain and a kinase domain. The overall goal of this renewal application is to elucidate the molecular
and cellular mechanisms of the Dcx gene family in neuronal migration and brain function. We will utilize knockout and
transgenic reporter mice combined with advanced live-cell imagingcapabilities and in vivo analysis that will synergize
to provide a powerful approach address this goal.
Aim 1. Test the degree of functional redundancy of Dcx homologues Dckl and Dck2 in neuronal migration and
brain development The function of Dcx in migration may be redundant with the Dckl and Dck2 genes in mouse. We
will analyze the degree of functional redundancy through the analysis of phenotype of Dckl and Dck2 single as well as
double and triple knockout mice and compare these results with siRNA-mediated gene knockdown approaches.
Aim 2. Test for defects in MT stabilization and nuclear-centrosomal coupling in Dcx-family gene inactivation.
Utilizing the approaches from Aim 1 and advanced live cell imaging techniques, we will test whether the Dcx gene
family is required for MT-dependent nuclear movement in neuronal migration.
Aim 3. Test for phosphorylation and phosphatase-dependent regulation of the MT effects of the Dcx gene family.
Our previous data has indicated strong negative-regulation of Dcx function through phosphorylation. We now have
genetic and biochemical data that actin-linked protein-phosphatase I and MT-linked Dckl/2 provide additional levels of
phosphorylation-dependent regulation. We will test the specificity of these interactions using the reagents generated
here and test their role in integratingthe microtubule and actin cytoskeletons required for stabilization of neuronal
growth cones.
Lay Summary: Mutations in doublecortin lead to severe neurological disorders in humans due to altered brain
development through unknown mechanisms. This study seeks to identify the function the family of doublecortin genes
using advanced molecular and cellular approaches.
由于神经元迁移障碍引起的皮质发育畸形越来越被认为是一种常见的
引起癫痫、智力迟钝和脑瘫的原因。双皮质素(OCX)基因是神经元的关键,
人类的迁移,因为突变导致男性X连锁无脑畸形和皮质下带状异位,
女性,产生严重的神经认知缺陷。我们确定了OCX基因,并在患有
这个条件。我们确定了它作为微管(MT)相关蛋白的作用,并参与了几个信号转导
通过磷酸化依赖机制的途径。我们还确定了Dcx在偶联
在迁移的核易位阶段,以微管依赖的方式将细胞核转移到中心体。DCX
是也包含Dckl和Dck 2的基因家族的一部分,每一个编码强脑表达的蛋白质,
匹配Dcx结构域和激酶结构域。本次更新申请的总体目标是阐明
以及Dcx基因家族在神经元迁移和脑功能中的细胞机制。我们将利用击倒,
转基因报告小鼠结合先进的活细胞成像能力和体内分析,
来提供一个强大的方法来实现这个目标。
目标1。测试Dcx同源物Dckl和Dck 2在神经元迁移中的功能冗余程度,
脑发育Dcx在小鼠迁移中的功能可能与Dck 1和Dck 2基因是冗余的。我们
将通过分析Dck 1和Dck 2单个以及
双敲除和三敲除小鼠,并将这些结果与siRNA介导的基因敲除方法进行比较。
目标2.检测Dcx家族基因失活中MT稳定性和核-中心体偶联的缺陷。
利用Aim 1的方法和先进的活细胞成像技术,我们将测试Dcx基因是否
家族是神经元迁移中MT依赖性核运动所必需的。
目标3。检测Dcx基因家族MT效应的磷酸化和磷酸酶依赖性调节。
我们以前的数据表明,Dcx功能通过磷酸化进行强烈的负调控。我们现在有
遗传和生物化学数据表明肌动蛋白连接的蛋白磷酸酶I和MT连接的Dckl/2提供了额外的水平,
磷酸化依赖性调节。我们将使用生成的试剂测试这些相互作用的特异性
在这里测试它们在整合微管和肌动蛋白细胞骨架中的作用,
生长锥
摘要:由于大脑改变,doublecortin突变导致人类严重的神经系统疾病
通过未知的机制发展。本研究旨在确定双皮质素基因家族的功能,
使用先进的分子和细胞方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JOSEPH G GLEESON其他文献
JOSEPH G GLEESON的其他文献
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{{ truncateString('JOSEPH G GLEESON', 18)}}的其他基金
Origins of Brain Somatic Mosaicism in Developmental Brain Disease
发育性脑疾病中脑体细胞嵌合的起源
- 批准号:
10466904 - 财政年份:2021
- 资助金额:
$ 33.75万 - 项目类别:
University of California San Diego Neuroscience Microscopy Imaging Core
加州大学圣地亚哥分校神经科学显微成像核心
- 批准号:
10524688 - 财政年份:2021
- 资助金额:
$ 33.75万 - 项目类别:
Origins of Brain Somatic Mosaicism in Developmental Brain Disease
发育性脑疾病中脑体细胞嵌合的起源
- 批准号:
10299502 - 财政年份:2021
- 资助金额:
$ 33.75万 - 项目类别:
Origins of Brain Somatic Mosaicism in Developmental Brain Disease
发育性脑疾病中脑体细胞嵌合的起源
- 批准号:
10669715 - 财政年份:2021
- 资助金额:
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Project I - Human genetics of meningomyelocele and risk mitigation by folic acid
项目 I - 脑膜脊髓膨出的人类遗传学和叶酸降低风险
- 批准号:
10300070 - 财政年份:2020
- 资助金额:
$ 33.75万 - 项目类别:
Developmental Mechanisms of Human Meningomyelocele
人类脑膜脊髓膨出的发生机制
- 批准号:
10533735 - 财政年份:2020
- 资助金额:
$ 33.75万 - 项目类别:
Developmental Mechanisms of Human Meningomyelocele
人类脑膜脊髓膨出的发生机制
- 批准号:
10300066 - 财政年份:2020
- 资助金额:
$ 33.75万 - 项目类别:
Developmental Mechanisms of Human Meningomyelocele
人类脑膜脊髓膨出的发生机制
- 批准号:
10154461 - 财政年份:2020
- 资助金额:
$ 33.75万 - 项目类别:
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