Mechanisms of DSCAM-mediated self-avoidance
DSCAM介导的自我回避机制
基本信息
- 批准号:10614602
- 负责人:
- 金额:$ 19.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdhesionsAdhesivesBindingBinding ProteinsBiological AssayBiologyC-terminalCadherinsCell AdhesionCell Adhesion MoleculesCell LineCell Surface ProteinsCell physiologyCellsComplementDataData SetDendritesDependenceDevelopmentDevelopmental ProcessDiseaseDown SyndromeDown Syndrome Cell Adhesion MoleculeElectroporationEndocytosisEventFascicleFutureGene ExpressionGenesGoalsHealthHumanIn VitroIndividualLearningMasksMediatingMembraneModelingMolecularMusMuscle fasciculationMutationNRCAM geneNervous SystemNeural RetinaNeuritesNeurodevelopmental DisorderNeuronsP-CadherinPathologyPositioning AttributeProcessProteinsPublic HealthRAPGEF2 geneResearchRetinaRoleSamplingSignal PathwaySignal TransductionSpecificitySurfaceSystemTestingTransfectionVariantVisionWorkautism spectrum disordercandidate identificationcell typedevelopmental diseaseexperimental studygenetic manipulationin vitro Assayin vivoinsightloss of functionmembermosaicmutantneuralneural circuitneurodevelopmentpharmacologicpreventreceptive fieldretinal neuron
项目摘要
PROJECT SUMMARY/ABSTRACT
Down syndrome cell adhesion molecule (DSCAM) is a member of the Ig superfamily of adhesion molecules
associated with Down syndrome and autism spectrum disorder (ASD). In the mouse retina, DSCAM is
responsible for neuronal self-avoidance at the cell type level; in Dscam-null retinas neurons lose their normal
spacing as they form clusters with other cells of the same subtype (homotypic) and their dendrites fasciculate
with each other. This is unusual, as DSCAM (like most homophilic adhesion molecules) drives adhesion and
cell clustering when expressed in heterologous cell lines. Previous work from the PI found that DSCAM
“masked” adhesion mediated by members of the cadherin superfamily and that masking in different cell
subtypes had a differential dependence on DSCAM’s PDZ-interacting C-terminus. The molecular mechanisms
of this masking remain unknown. Here we propose experiments to define these molecular mechanisms. We
hypothesize that DSCAM masks diverse cell adhesion molecules (CAMs), not only cadherin adhesion, and that
the differential dependence on C-terminal interactions reflect different cell type specific adhesion systems. In
Specific Aim 1 we will use an in vitro assay of adhesive masking to test candidate signaling pathways and
cellular processes. This assay takes advantage of homophilic interactions between CAMs in a neuron and on a
bead, which results in clustering of the neuronal CAM around the bead. Homophilic DSCAM interactions
prevent the clustering of other CAMs (e.g., cadherins). We will use a variety of pharmacological and genetic
manipulations to test candidate mechanisms in this assay, and we will verify findings with in vivo
electroporation. In Specific Aim 2, we will test our hypothesis that differential clustering and fasciculation in C-
terminal mutants reflects different sets of cell-type-specific CAMs, and DSCAM’s PDZ-interacting motif is only
required to mask a subset of CAMs. To do this, we will leverage new datasets describing cell type specific
gene expression to identify candidate CAMs expressed in cell types that either require DSCAMs C-terminal
PDZ interactions for normal spacing or do not require DSCAM’s C-terminus. Using in vivo electroporation into
retina-specific conditional loss of function mutants and into C-terminal truncation mutants, we will test if these
CAMs require DSCAM’s C-terminus for masking. In Specific Aim 3, we will test ASD-associated DSCAM
mutations in the neuron/bead assay by rescuing masking in Dscam-deficient neurons. Cell adhesion has
emerged as a major theme in ASD pathology and DSCAM is positioned as a key regulator of this process. The
completion of these studies will provide crucial first steps towards understanding how DSCAM dynamically
regulates adhesive systems during development to prevent excessive adhesion while allowing appropriate
CAM interactions, addressing fundamental questions in retinal neural development with implications in
neurodevelopmental disorders like ASD.
项目总结/文摘
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Andrew Garrett其他文献
Andrew Garrett的其他文献
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{{ truncateString('Andrew Garrett', 18)}}的其他基金
Mechanisms of Cell Adhesion Molecule Function in Retinal Development
视网膜发育中细胞粘附分子功能的机制
- 批准号:
10650788 - 财政年份:2021
- 资助金额:
$ 19.25万 - 项目类别:
Mechanisms of Cell Adhesion Molecule Function in Retinal Development
视网膜发育中细胞粘附分子功能的机制
- 批准号:
10297694 - 财政年份:2021
- 资助金额:
$ 19.25万 - 项目类别:
Intracellular signaling by DSCAM during retinal development
视网膜发育过程中 DSCAM 的细胞内信号传导
- 批准号:
8198040 - 财政年份:2011
- 资助金额:
$ 19.25万 - 项目类别:
Intracellular signaling by DSCAM during retinal development
视网膜发育过程中 DSCAM 的细胞内信号传导
- 批准号:
8332418 - 财政年份:2011
- 资助金额:
$ 19.25万 - 项目类别:
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