Functions of membrane deforming-proteins during neuronal development
膜变形蛋白在神经元发育过程中的功能
基本信息
- 批准号:7940411
- 负责人:
- 金额:$ 21.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-03-15 至 2010-07-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAllelesAxonBindingBinding ProteinsBiochemicalBiologicalBiological ProcessBrainBrain-Derived Neurotrophic FactorBundlingC-terminalCell LineCell physiologyCellsCouplingCytoskeletonDataDendritesDendritic SpinesDevelopmentDynaminEndocytosisF-ActinFamilyFilopodiaGenesGenetic screening methodGrowthHumanIn VitroKnock-outLengthMediatingMembraneMental RetardationMicrotubulesModelingMolecularMolecular ConformationMorphogenesisMusMutateN-terminalNeoplasm MetastasisNeurogliaNeuronsPathologyPatternPlayProcessProtein FamilyProteinsProteomicsRadialRegulationRoleSH3 DomainsSignal PathwaySignal TransductionStructureSystemTRIP10 geneTestingWorkchromosome 3p deletion syndromechromosome 3p duplication syndromeextracellularimprovedin vivoinsightmigrationneurite growthneuron developmentnovelpolymerizationprotein functionpublic health relevancesmall hairpin RNA
项目摘要
DESCRIPTION (provided by applicant): During brain development, proper neuronal migration and morphogenesis is critical for the establishment of functional circuits. Both neuronal migration as well as axon and dendrite differentiation requires extensive membrane remodeling and cytoskeleton dynamics. Until recently, most studies in this field have focused on proteins directly regulating microtubules and actin cytoskeletal dynamics. However, recent evidence suggests that a new class of molecules directly controlling membrane deformation and dynamics (BAR-like superfamily subdivided into BAR / N-BAR, F-BAR, and I-BAR domains) regulate important cell biological processes ranging from membrane invagination (endocytosis) to membrane protrusion (filopodia formation). The most recently identified, the F-BAR subfamily, has mostly been studied in cell lines or more reductionist in vitro systems and the 23 human genes of this sub-family have poorly characterized functions in vivo. Recently, a large deletion in one of these genes called srGAP3 or MEGAP was shown to cause a familial form of severe mental retardation called 3p- syndrome suggesting that some F-BAR containing proteins might play important functions during brain development. Furthermore, several other genes containing either GAP domains or BAR domains such as Oligophrenin-1 (Billuart et al., 1998) and OCRL-1 (Nussbaum et al. 1997) have been found to be mutated in severe forms of mental retardation. Therefore, our work on srGAP2 will provide a framework to improve our understanding of the function of proteins sharing similar domains during cortical development. We recently initiated the study of a F-BAR domain-containing protein called srGAP2 and found that this protein is a novel regulator of neurite growth and branching (Guerrier et al., 2009). This function requires its N- terminal F-BAR domain. Surprisingly, unlike previously characterized F-BAR domains which regulate membrane invagination and endocytosis, the F-BAR domain of srGAP2 induces filopodia-like membrane protrusions in COS7 cells and cortical neurons resembling those induced by I-BAR domains in vitro and in vivo. Importantly our structure- function analysis led us hypothesize that the regulation of membrane deformation by F-BAR domain-containing proteins plays critical roles during neuronal morphogenesis. We further hypothesize that srGAP2 activation involves release from an autoinhibitory conformation through binding of protein interactors to its SH3 domain. We will test this hypothesis using multiple approaches divided in three specific aims: in Aim1, we will identify the molecular mechanisms regulating the function of srGAP2 in cortical neurons by using combinations of biochemical and cell biological approaches in order to identify and characterize the binding partners of its SH3 domain which is critical for the regulation of srGAP2 activity during neuronal migration and morphogenesis. In Aim 2, we will explore the function of srGAP2 in axon/dendrite branching induced by well-characterized branching factors such as Slit1/2 and BDNF in vitro and in vivo. In Aim 3, we will test the requirement of srGAP2 for proper neuronal migration and morphogenesis in vivo using a recently characterized gene-trap allele of srGAP2. We will also test the functional redundancy of srGAP2 and srGAP3 which share both structural organization and developmental expression patterns.
PUBLIC HEALTH RELEVANCE: During brain development, proper neuronal migration and morphogenesis is critical for the establishment of functional neuronal circuits. Here we propose to study the function of a novel family of proteins regulating membrane deformation (F-BAR proteins) in neuronal migration and morphogenesis. This work will provide important new insights into the developmental mechanisms leading to a wide range of pathologies including severe mental retardation (3p- syndrome).
描述(申请人提供):在大脑发育过程中,适当的神经元迁移和形态发生对功能回路的建立至关重要。神经元的迁移以及轴突和树突的分化都需要广泛的膜重建和细胞骨架动力学。直到最近,这一领域的大多数研究都集中在直接调节微管和肌动蛋白细胞骨架动力学的蛋白质上。然而,最近的证据表明,一类新的直接控制膜变形和动力学的分子(棒状超家族细分为bar/N-bar、F-bar和I-bar结构域)调节从膜内陷(内吞)到膜突起(丝足形成)等重要的细胞生物学过程。最近发现的F-bar亚家族,大多是在体外细胞系或更多的还原剂系统中进行研究的,这个亚家族中的23个人类基因在体内的功能很差。最近,其中一种名为srGAP3或MEGAP的基因的大量缺失被证明会导致一种名为3P综合征的家族性严重智力低下,这表明一些含有F-bar的蛋白质可能在大脑发育过程中发挥重要作用。此外,还发现了其他几个含有GAP结构域或Bar结构域的基因,如寡聚精神蛋白-1(Bluart等人,1998)和OCRL-1(Nussbaum等人。1997年)被发现突变为严重形式的精神发育迟滞。因此,我们在SRGAP2上的工作将为我们提供一个框架,以提高我们对共享相似结构域的蛋白质在皮质发育过程中的功能的理解。我们最近开始了一种名为SRGAP2的含有F-bar结构域的蛋白质的研究,并发现这种蛋白质是一种新的轴突生长和分支调节因子(Guerrier等人,2009年)。此功能需要其N端F-BAR结构域。令人惊讶的是,与先前描述的调节膜内陷和内吞的F-bar结构域不同,SRGAP2的F-bar结构域在COS7细胞和皮质神经元中诱导丝状足状突起,类似于I-bar结构域在体外和体内诱导的膜突起。重要的是,我们的结构-功能分析引导我们假设,含有F-bar结构域的蛋白对膜变形的调节在神经元形态发生过程中起着关键作用。我们进一步假设,SRGAP2的激活涉及通过蛋白质相互作用物与其SH3结构域结合而从自抑制构象中释放出来。我们将使用分为三个特定目标的多种方法来验证这一假说:在Aim1中,我们将结合生化和细胞生物学方法确定SRGAP2在皮质神经元中功能的分子机制,以确定和表征其SH3结构域的结合伙伴,该结合伙伴在神经元迁移和形态发生过程中对SRGAP2活性的调节至关重要。在目标2中,我们将在体内外研究SRGAP2在Slit1/2和BDNF等已知的分支因子诱导的轴突/树突分支中的作用。在目标3中,我们将使用最近鉴定的SRGAP2的基因陷阱等位基因来测试SRGAP2对体内正常的神经元迁移和形态发生的需求。我们还将测试SRGAP2和srGAP3的功能冗余,它们都具有结构组织和发育表达模式。
公共卫生相关性:在大脑发育过程中,适当的神经元迁移和形态发生对于建立功能神经元回路至关重要。在这里,我们建议研究一类新的调控膜变形的蛋白质家族(F-bar蛋白)在神经元迁移和形态发生中的作用。这项工作将对导致包括严重精神发育迟滞(3P综合征)在内的广泛病理的发育机制提供重要的新见解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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FRANCK POLLEUX其他文献
FRANCK POLLEUX的其他文献
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{{ truncateString('FRANCK POLLEUX', 18)}}的其他基金
Development, maintenance, and human-specific evolution of cortical circuits
皮质回路的发育、维护和人类特异性进化
- 批准号:
10450230 - 财政年份:2022
- 资助金额:
$ 21.19万 - 项目类别:
Development, maintenance, and human-specific evolution of cortical circuits
皮质回路的发育、维护和人类特异性进化
- 批准号:
10612936 - 财政年份:2022
- 资助金额:
$ 21.19万 - 项目类别:
Role of ER-mitochondria contacts in dendritic Ca2+ homeostasis, synaptic integration and circuit function
内质网-线粒体接触在树突 Ca2 稳态、突触整合和电路功能中的作用
- 批准号:
9926321 - 财政年份:2019
- 资助金额:
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2012 Neural Development Gordon Research Conference
2012 神经发展戈登研究会议
- 批准号:
8314416 - 财政年份:2012
- 资助金额:
$ 21.19万 - 项目类别:
Functions of membrane deforming-proteins during neuronal development
膜变形蛋白在神经元发育过程中的功能
- 批准号:
8212412 - 财政年份:2010
- 资助金额:
$ 21.19万 - 项目类别:
Cellular and molecular mechanisms underlying the function of SRGAP2 during synaptic development
突触发育过程中 SRGAP2 功能的细胞和分子机制
- 批准号:
9328162 - 财政年份:2010
- 资助金额:
$ 21.19万 - 项目类别:
Functions of membrane deforming-proteins during neuronal development
膜变形蛋白在神经元发育过程中的功能
- 批准号:
8241990 - 财政年份:2010
- 资助金额:
$ 21.19万 - 项目类别:
Functions of membrane deforming-proteins during neuronal development
膜变形蛋白在神经元发育过程中的功能
- 批准号:
8174213 - 财政年份:2010
- 资助金额:
$ 21.19万 - 项目类别:
Functions of membrane deforming-proteins during neuronal development
膜变形蛋白在神经元发育过程中的功能
- 批准号:
8432487 - 财政年份:2010
- 资助金额:
$ 21.19万 - 项目类别:
Cellular and molecular mechanisms underlying the function of SRGAP2 during synaptic development
突触发育过程中 SRGAP2 功能的细胞和分子机制
- 批准号:
9176936 - 财政年份:2010
- 资助金额:
$ 21.19万 - 项目类别:
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