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:7591684
- 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 ProteinActinsAddressBiochemicalBrainCell NucleusCellsCentrosomeCerebral PalsyCortical MalformationCouplingCyclin-Dependent Kinase 5CytoskeletonDataDefectDevelopmentEpilepsyFamilyFemaleGene FamilyGene SilencingGenerationsGenesGeneticGoalsGrowth ConesHomologous GeneHumanImaging TechniquesImmigrationKnock-outKnockout MiceLeadLifeLinkMasksMediatingMental RetardationMicrotubule StabilizationMicrotubule-Associated ProteinsMicrotubulesMiller-Dieker SyndromeMolecularMovementMusMutationNeurocognitive DeficitNeuronal Migration DisorderNeuronsNuclearNuclear TranslocationPathway interactionsPatientsPhasePhenotypePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPhysical condensationProcessProtein DephosphorylationProtein phosphataseProteinsReagentRegulationReporterReportingRoleSignal PathwaySiteSmall Interfering RNASpecificitySyndromeTestingTransgenic OrganismsWorkcellular imagingin vivolink proteinlissencephalymalemigrationnervous 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.
由神经元迁移障碍引起的皮质发育畸形日益被认为是一种常见的
癫痫、智力低下和脑性瘫痪的原因。双重皮质素(Ocx)基因对神经细胞起关键作用
人类的迁移,因为突变导致男性X连锁无脑和皮质下带异位
女性,产生严重的神经认知缺陷。我们鉴定了OCX基因,并在患有OCX的患者中发现了突变
这种情况。我们确定了它作为微管相关蛋白的作用以及它参与了几个信号转导。
通过磷酸化依赖机制的通路。我们还确定了DCX在偶联
在迁移的核移位阶段,核以微管依赖的方式从核到中心体。DCX
是一个基因家族的一部分,该基因家族还包含Dck 1和Dck 2,每个基因都编码一种与大脑表达紧密的蛋白质
匹配DCX结构域和一个激活域。这一更新申请的总体目标是阐明分子
以及DCX基因家族在神经元迁移和脑功能中的细胞机制。我们将利用淘汰赛和
转基因报告鼠结合先进的活细胞成像能力和体内分析将协同
为了提供一种强大的方法来实现这一目标。
目的1.检测DCX同系物Dck 1和Dck 2在神经元迁移和分化过程中的功能冗余度。
在小鼠脑发育中,DCX在迁移过程中的功能可能与DCK1和DKK2基因冗余。我们
将通过分析DCK1和DKK2单基因的表型以及
两次和三次基因敲除小鼠,并将这些结果与siRNA介导的基因敲除方法进行比较。
目的2.检测DCX家族基因失活的MT稳定性缺陷和核-中心体偶联缺陷。
利用AIM 1的方法和先进的活细胞成像技术,我们将检测DCX基因
在神经元迁移中,家族是MT依赖性核运动所必需的。
目的3.检测DCX基因家族对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,通过磷酸化对DCX功能进行了强烈的负调控。我们现在有
遗传和生化数据表明,肌动蛋白连接的蛋白磷酸酶I和MT连接的DKCL/2提供了额外的水平
依赖于磷酸化的调节。我们将使用生成的试剂来测试这些相互作用的特异性
在这里测试它们在整合神经元稳定所需的微管和肌动蛋白细胞骨架中的作用
生长锥体。
莱茵综述:双重皮质素突变导致人类大脑改变而导致严重的神经疾病
通过未知的机制发展。这项研究试图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:
$ 33.75万 - 项目类别:
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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