Role of Cyclins in Brain Construction and Interneuron Genesis
细胞周期蛋白在大脑构建和中间神经元生成中的作用
基本信息
- 批准号:8920677
- 负责人:
- 金额:$ 4.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-30 至 2016-08-19
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAnxietyAnxiety DisordersAutistic DisorderBehaviorBehavior DisordersBiochemistryBrainCell Culture TechniquesCell CycleCell Cycle ProteinsCell ProliferationCell divisionCellsCentrosomeCerebral cortexCognitionCognition DisordersComplexCortical MalformationCyclin D1CyclinsDataDevelopmentDiseaseElectroporationEmbryoEpilepsyEquilibriumEtiologyExhibitsFellowshipFunctional disorderG1 PhaseGenerationsGeneticGlycogen Synthase Kinase 3GoalsHealthHumanImageImmunohistochemistryIn VitroInterneuronsKnockout MiceKnowledgeLabelLaboratoriesLeadLightLinkMeasuresMedialMental disordersMolecularMolecular ProfilingMusMutateMutationNeocortexNeurogliaNeurosciencesOutcomeParvalbuminsPatientsPhosphorylationPhosphorylation SitePlayPositioning AttributeProcessProductionProsencephalonProteinsRadialRegulationRetroviridaeRoleS PhaseSchizophreniaSliceSomatostatinStem cellsTechnologyTimeVentricularWorkautism spectrum disorderbasebehavioral studybrain malformationcyclin D2daughter celldensitydesigneffective therapyin uteroin vitro Assayin vivoknockout animalmature animalmutantneocorticalnerve stem cellneurogenesisneuropsychiatrynovel therapeutic interventionprematureprogenitorprotein degradationrelating to nervous systemresearch studysubventricular zonetime use
项目摘要
DESCRIPTION (provided by applicant):
Deficits in interneuron generation and function are thought to underlie the pathophysiology of epilepsy and cognitive disorders including schizophrenia, autism spectrum, and anxiety. To understand interneuron development and brain construction we will compare and contrast the actions of G1-phase cyclin D2 (cD2) versus cyclin D1 (cD1), cell cycle proteins that regulate passage through mid-G1 toward S-phase. These D- type cyclins are expressed in different progenitor pools of the embryonic mouse neocortex and the medial ganglionic eminence (MGE), the origin of cortical parvalbumin (PV)- and somatostatin (SST)-expressing interneurons. We previously showed that cD1 is highly enriched in radial glial cells in the ventricular zone, while cD2 predominates in intermediate progenitor cells in the subventricular zone (SVZ) of the neocortex and MGE. Cyclin D2 knockout mouse embryos exhibit small cortices, prolonged G1 duration, and premature cell cycle exit. Adult animals deficient in cD2 show disproportionate reductions in PV-positive interneurons with preserved SST interneuron densities, while cD1 knockout animals do not exhibit such deficits. Thus, cD2 expression is crucial for proliferation and production of specific subpopulations of interneurons. The mechanisms by which cD2 and cD1 differentially regulate neural proliferation are poorly understood. Recently, we identified human mutations in known phosphorylation sites on cD2 that result in severe cortical malformations, indicating the importance of phosphorylation of this molecule for brain construction. This fellowship application will explore the role that phosphorylation of cD2 versus cD1 plays in embryonic forebrain neurogenesis. Based on our previous work, we hypothesize that cD2 and cD1 are differentially utilized in embryonic brain development so that cD2 promotes SVZ symmetric cell divisions. We will employ in utero electroporation, ex vivo slice electroporation, and time-lapse imaging to examine the role of cD2 in proliferation and promotion of asymmetric versus symmetric cell divisions. We will also use pair-cell in vitro assays and in vivo genetic mosaic analysis with double markers (MADM) to assess asymmetric versus symmetric division outcomes in the presence or absence of cD2. The proposed experiments will advance our understanding of precisely how these D-type cyclins regulate proliferation within the cerebral cortex and the MGE, illuminating how interneuron subtypes are generated in the MGE. These studies will contribute to the ultimate goal to devise more effective therapies for neuropsychiatric disorders.
描述(由申请人提供):
中间神经元生成和功能缺陷被认为是癫痫和认知障碍(包括精神分裂症、自闭症谱系和焦虑)的病理生理学基础。为了了解中间神经元的发育和脑结构,我们将比较和对比G1期细胞周期蛋白D2(CD2)和细胞周期蛋白D1(CD1)的作用,这是一种细胞周期蛋白,调节通过G1中期进入S阶段。这些D型细胞周期蛋白在胚胎小鼠新皮质和内侧神经节隆起(MGE)的不同祖细胞池中表达,MGE是皮质小白蛋白(PV)和生长抑素(SST)表达的中间神经元的来源。我们先前的研究表明,CD1在脑室区域的放射状胶质细胞中高度丰富,而CD2在新皮质和MGE的脑室下区(SVZ)的中间前体细胞中占主导地位。Cyclin D2基因敲除的小鼠胚胎皮质较小,G1期延长,细胞周期提前退出。缺乏CD2的成年动物表现出不成比例的PV阳性中间神经元减少,而SST中间神经元密度保持不变,而CD1基因敲除的动物则不表现出这种缺陷。因此,CD2的表达对特定的中间神经元亚群的增殖和产生至关重要。CD2和CD1不同地调控神经增殖的机制尚不清楚。最近,我们发现了CD2上已知的磷酸化位点的突变,这些突变会导致严重的皮质畸形,表明这种分子的磷酸化对脑结构的重要性。这项奖学金申请将探索CD2和CD1的磷酸化在胚胎前脑神经发生中所起的作用。基于我们以前的工作,我们假设CD2和CD1在胚胎脑发育中的作用是不同的,因此CD2促进SVZ对称细胞分裂。我们将使用宫内电穿孔,体外切片电穿孔,和时间推移成像来检测CD2在增殖和促进不对称和对称细胞分裂中的作用。我们还将使用体外成对细胞分析和体内双标记遗传马赛克分析(MADM)来评估存在或不存在CD2的不对称和对称分裂结果。拟议的实验将促进我们对这些D型细胞周期蛋白如何调控大脑皮层和MGE内的增殖的确切理解,阐明MGE中中间神经元亚型是如何产生的。这些研究将有助于为神经精神障碍设计更有效的治疗方法的最终目标。
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)
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Kristin Giamanco其他文献
Kristin Giamanco的其他文献
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{{ truncateString('Kristin Giamanco', 18)}}的其他基金
Role of Cyclins in Brain Construction and Interneuron Genesis
细胞周期蛋白在大脑构建和中间神经元生成中的作用
- 批准号:
8647316 - 财政年份:2013
- 资助金额:
$ 4.99万 - 项目类别:
Role of Cyclins in Brain Construction and Interneuron Genesis
细胞周期蛋白在大脑构建和中间神经元生成中的作用
- 批准号:
8744640 - 财政年份:2013
- 资助金额:
$ 4.99万 - 项目类别:
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