Quantitative serial ultrastructural analysis of protocadherin containing synapses
含有原钙粘蛋白的突触的定量连续超微结构分析
基本信息
- 批准号:9328160
- 负责人:
- 金额:$ 8.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-08 至 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdhesionsAdhesivesAffectAffinityAnimal ModelAntibodiesAutistic DisorderBindingCadherinsCell AdhesionCell Adhesion MoleculesCell CommunicationCell surfaceCellsCytoplasmic TailDefectDendritesDevelopmentElectronsEndocytosisEpigenetic ProcessExhibitsExtracellular DomainFamilyFreeze SubstitutionFunctional disorderFutureGene ClusterGene TargetingGenesHippocampus (Brain)Immunoelectron MicroscopyIndividualLabelLateralLengthLightLinkMediatingMembraneMental RetardationMicroscopicModificationMorphologyMutationN-CadherinNervous system structureNeurodevelopmental DisorderNeuronsPerforationProcessPropertyRattusRecruitment ActivityRoleSignal TransductionSpecific qualifier valueSpecificitySpecimenSurfaceSynapsesSynaptic CleftSystemThickTimedensityimmunoreactivityinterestknockout animalneural circuitneurodevelopmentpostsynapticpresynapticsynaptic functiontrafficking
项目摘要
Project Summary
Cell adhesion molecules are critical for synaptic development in the CNS. They mediate homophilic binding
and trans-synaptic interactions, both stabilizing synapses and specifying connectivity. Defects in synaptic
adhesion are thought to accompany some neurodevelopmental disorders such as autism and mental
retardation. The discovery of the clustered and non-clustered protocadherins (Pcdhs), the largest family of
adhesion molecules, generated great interest for their potential role as synaptic specifiers. Our studies of one
Pcdh subfamily (the Pcdh-γs) point to a much different role for the Pcdhs in cellular interactions at the synapse.
We showed that Pcdh-γs have homophilic binding specificity at the cell surface, consistent with a role in cell-
cell interactions, but we also found that both endogenous and expressed Pcdh-γs are mostly found in
intracellular compartments rather than the cell surface. This contrasted with the surface distribution of classical
cadherins. In further support of a nonconventional role for Pcdhs, we identified specific targeting signals in the
cytoplasmic domains of Pcdh-γs that mediate their retention or endocytosis in the endolysosome system. The
Pcdh intracellular distribution and the homophilic specificity of their extracellular domains represent a paradox:
How can Pcdhs participate in cell-cell interactions if they are not at the surface? There are two possibilities for
how Pcdh cell-cell engagement might affect the synapse. The dendrite self-avoidance activity of Pcdh-γs
suggests that they might mediate avoidance at synapses that express matching Pcdhs, which would implicate
them in synaptic destabilization/pruning during development. Alternatively, they may have a pro-adhesive role
at the synapse, resulting in synaptic stabilization and maturation. Given the emerging importance of Pcdhs in
synaptic neurodevelopmental disorders such as autism, which has a clear synaptic component, it will be
important that we differentiate between the two possibilities. In this proposal we will address for the first time
how Pcdhs might affect synaptic development by conducting quantitative serial immuno-electron microscopic
analysis of Pcdh synaptic localization and how their trafficking associates with synaptic development and
morphology. We will also begin studies of two non-clustered protocadherins, Pcdh-8 and Pcdh-10, which have
not yet been characterized at the synaptic level.
项目摘要
细胞黏附分子是中枢神经系统突触发育的关键分子。它们介导了嗜同性结合
以及跨突触的相互作用,既稳定突触又指定连接性。突触的缺陷
粘连被认为伴随着一些神经发育障碍,如自闭症和精神障碍。
智力迟缓。簇状和非簇状原钙粘附素(Pcdhs)的发现
黏附分子因其作为突触说明物的潜在作用而引起了极大的兴趣。我们对一个人的研究
Pcdh亚家族(Pcdh-γS)指出,Pcdhs在突触的细胞相互作用中扮演着非常不同的角色。
我们发现PCDH-γS在细胞表面具有亲和性结合特异性,与在细胞-DNA中的作用一致。
细胞相互作用,但我们也发现,无论是内源性的还是表达的pCDH-γS都大多存在于
细胞内的隔室而不是细胞表面。这与经典的表面分布形成了鲜明的对比。
钙粘附素。为了进一步支持Pcdhs的非常规作用,我们在
Pcdh-γS的胞质结构域,介导其在内溶酶系统中的滞留或内吞作用。这个
Pcdh在细胞内的分布和其胞外结构域的同嗜性特异性表现出一个悖论:
如果Pcdh不在表面,它们如何参与细胞与细胞之间的相互作用?有两种可能性
Pcdh细胞-细胞接触如何影响突触。Pcdh-γS的树枝自回避活性
这表明它们可能在表达匹配的Pcdhs的突触上调节回避,这将意味着
在发育过程中,它们处于突触不稳定/修剪状态。或者,它们可能起到促进粘连的作用。
在突触,导致突触稳定和成熟。鉴于方案和方案的重要性正在显现
突触神经发育障碍,如自闭症,它有明确的突触成分,它将是
重要的是,我们要区分这两种可能性。在这项提案中,我们将第一次解决
Pcdhs如何通过定量系列免疫电子显微镜影响突触发育
分析Pcdh突触定位及其运输与突触发育和功能的关系
形态学。我们还将开始研究两个非聚集的原钙粘附素,Pcdh-8和Pcdh-10,它们已经
还没有在突触水平上被描述出来。
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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{{ truncateString('GREG R PHILLIPS', 18)}}的其他基金
Mechanism of protocadherin-mediated self-avoidance
原钙粘蛋白介导的自我回避机制
- 批准号:
10291761 - 财政年份:2021
- 资助金额:
$ 8.24万 - 项目类别:
Mechanisms of adhesion and recognition at CNS synapses
中枢神经系统突触的粘附和识别机制
- 批准号:
6767464 - 财政年份:2004
- 资助金额:
$ 8.24万 - 项目类别:
Mechanisms of adhesion and recognition at CNS synapses
中枢神经系统突触的粘附和识别机制
- 批准号:
6855109 - 财政年份:2004
- 资助金额:
$ 8.24万 - 项目类别:
CADHERIN MEDIATED ADHESION AT THE CNS SYNAPTIC JUNCTION
钙粘蛋白介导的中枢神经系统突触连接处的粘附
- 批准号:
6186730 - 财政年份:2000
- 资助金额:
$ 8.24万 - 项目类别:
CADHERIN MEDIATED ADHESION AT THE CNS SYNAPTIC JUNCTION
钙粘蛋白介导的中枢神经系统突触连接处的粘附
- 批准号:
2864933 - 财政年份:1999
- 资助金额:
$ 8.24万 - 项目类别:
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