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:8647316
- 负责人:
- 金额:$ 5.22万
- 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 2016-09-29
- 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 PhaseGenerationsGeneticGoalsHumanImageImmunohistochemistryIn VitroInterneuronsKnockout MiceKnowledgeLabelLaboratoriesLeadLightLinkMeasuresMedialMental disordersMolecularMolecular ProfilingMusMutateMutationNeocortexNeurogliaNeurosciencesOutcomeParvalbuminsPatientsPhosphorylationPhosphorylation SitePlayPositioning AttributeProcessProductionProsencephalonProteinsRadialRegulationRetroviridaeRoleS phaseSchizophreniaSliceSomatostatinTechnologyTimeVentricularWorkautism spectrum disorderbasebrain malformationcyclin D2daughter celldensitydesigneffective therapyin uteroin vitro Assayin vivoknockout animalmature animalmutantneocorticalnerve stem cellneurogenesisneuropsychiatrynovel therapeutic interventionprematureprogenitorprotein degradationpublic health relevancerelating to nervous systemresearch studystem cellssubventricular 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的缺陷被认为是癫痫和认知障碍(包括精神分裂症、自闭症谱系和焦虑症)的病理生理学基础。为了了解中间神经元的发育和大脑的构造,我们将比较和对比G1期细胞周期蛋白D2(CD 2)与细胞周期蛋白D1(CD 1)的作用,细胞周期蛋白调节通过中期G1期向S期的通道。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)的不同祖细胞库中表达,内侧神经节隆起是皮质小白蛋白(PV)和生长抑素(SST)表达中间神经元的起源。我们以前表明,cD 1是高度富集在径向胶质细胞在脑室区,而cD 2占主导地位的中间祖细胞在脑室下区(SVZ)的新皮质和MGE。细胞周期蛋白D2基因敲除小鼠胚胎表现出小皮质,G1期延长,和过早的细胞周期退出。缺乏cD 2的成年动物表现出不成比例的减少,在PV阳性的中间神经元与保存SST中间神经元密度,而cD 1敲除动物不表现出这样的赤字。因此,cD 2表达对于中间神经元的特定亚群的增殖和产生至关重要。 cD 2和cD 1差异调节神经增殖的机制知之甚少。最近,我们在cD 2上已知的磷酸化位点发现了导致严重皮质畸形的人类突变,表明了这种分子磷酸化对大脑构建的重要性。这项奖学金申请将探讨的作用,磷酸化的cD 2与cD 1发挥胚胎前脑神经发生。基于我们以前的工作,我们假设,cD 2和cD 1的差异利用胚胎脑发育,使cD 2促进SVZ对称细胞分裂。我们将采用在子宫内电穿孔,离体切片电穿孔,和延时成像检查的作用,CD 2的增殖和促进不对称与对称的细胞分裂。我们还将使用双标记物(MADM)进行体外细胞对试验和体内遗传嵌合体分析,以评估在存在或不存在cD 2的情况下的不对称与对称分裂结果。拟议的实验将推进我们对这些D型细胞周期蛋白如何调节大脑皮层和MGE内增殖的精确理解,阐明MGE中如何产生中间神经元亚型。这些研究将有助于设计更有效的治疗神经精神疾病的最终目标。
项目成果
期刊论文数量(0)
专著数量(0)
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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:
8920677 - 财政年份:2013
- 资助金额:
$ 5.22万 - 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:
$ 5.22万 - 项目类别:
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