Targeted inactivation of the clustered protocadherin genes in zebrafish

斑马鱼中簇状原钙粘蛋白基因的靶向失活

基本信息

  • 批准号:
    8052732
  • 负责人:
  • 金额:
    $ 7.63万
  • 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:
    2010-03-26 至 2013-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The function of the central nervous system (CNS) is dependent upon the establishment of synaptic junctions during development and the proper patterning of neuronal connectivity to generate functional circuits. Failure to establish the appropriate synaptic connections can result in severe disorders of the nervous system, including mental retardation, autism, schizophrenia and depression. Thus, it is essential to understand the molecular mechanisms responsible both for assembling the synaptic junction, and for directing the selection of functionally appropriate synaptic partners. Our long-term goal is to understand the cellular and molecular mechanisms responsible for synaptic assembly and selection in the vertebrate CNS. To address these questions, we are using in vivo multiphoton imaging of synaptogenesis in the developing zebrafish CNS, focusing on the roles played by 3-protocadherins. The embryonic zebrafish is an ideal system in which to address these questions, as embryos are transparent, develop externally and rapidly, and have a relatively simple and highly stereotyped CNS. In addition, the recent development of site-specific modification of the genome through the use of engineered zinc-finger nucleases (ZFNs) will enable the efficient production of zebrafish lines that harbor mutations in genes of interest. In this exploratory R03 proposal, we will use the emerging ZFN technology to generate lines of zebrafish carrying lesions in each of the 3-protocadherin genes present in zebrafish, pcdh13 and pcdh23. Having generated and validated these lines, we will also perform an initial phenotypic analysis. As targeted deletion of pcdh3 in mice results in extensive neuronal death throughout the CNS, we will first assess the levels of programmed cell death occurring in the developing nervous system. We will also characterize any effects on the organization of the nervous system, using wholemount immunocytochemistry to label the early scaffold of axon tracts. Finally, we will use both immunocytochemistry and live imaging to identify any defects in the formation or maintenance of synaptic vesicle clusters. The pcdh3 mutant lines produced from this work will be invaluable resources for investigating both the cellular and developmental function of Pcdh3, allowing us to take full advantage of the zebrafish model system. PUBLIC HEALTH RELEVANCE: The formation of synaptic junctions and their patterning into circuits of appropriately connected neuronal populations is essential for the normal development of the central nervous system. Defects in these events can have a profound influence on human behavior, and may underlie numerous disorders of the nervous system, including autism, mental retardation and schizophrenia. The results of our studies will greatly enhance our knowledge of 3-protocadherin function in neural circuit assembly, and will provide a strong foundation for developing novel therapeutic strategies for addressing these disorders. These investigations will also contribute to a firm understanding of the developmental mechanisms responsible for synaptogenesis, which could be essential for creating effective approaches to promote repair after brain or spinal cord injuries.
描述(由申请人提供):中枢神经系统(CNS)的功能取决于发育过程中突触连接的建立以及神经元连接的正确模式以生成功能回路。未能建立适当的突触连接可能会导致严重的神经系统疾病,包括智力低下、自闭症、精神分裂症和抑郁症。因此,了解负责组装突触连接和指导选择功能上适当的突触伙伴的分子机制至关重要。我们的长期目标是了解脊椎动物中枢神经系统中负责突触组装和选择的细胞和分子机制。为了解决这些问题,我们正在发育中的斑马鱼中枢神经系统中使用突触发生的体内多光子成像,重点关注 3-原钙粘蛋白所发挥的作用。胚胎斑马鱼是解决这些问题的理想系统,因为胚胎是透明的,外部发育迅速,并且具有相对简单和高度定型的中枢神经系统。此外,最近通过使用工程锌指核酸酶(ZFN)对基因组进行位点特异性修饰的发展将能够有效生产含有感兴趣基因突变的斑马鱼品系。在这个探索性的 R03 提案中,我们将使用新兴的 ZFN 技术来生成在斑马鱼中存在的每个 3-原钙粘蛋白基因 pcdh13 和 pcdh23 中携带病变的斑马鱼品系。生成并验证这些品系后,我们还将进行初始表型分析。由于小鼠中 pcdh3 的靶向缺失会导致整个中枢神经系统广泛的神经元死亡,因此我们将首先评估发育中的神经系统中发生的程序性细胞死亡的水平。我们还将使用整体免疫细胞化学来标记轴突束的早期支架,从而表征对神经系统组织的任何影响。最后,我们将使用免疫细胞化学和实时成像来识别突触小泡簇形成或维持中的任何缺陷。这项工作产生的 pcdh3 突变系将成为研究 Pcdh3 的细胞和发育功能的宝贵资源,使我们能够充分利用斑马鱼模型系统。 公共卫生相关性:突触连接的形成及其形成适当连接的神经元群回路的模式对于中枢神经系统的正常发育至关重要。这些事件中的缺陷会对人类行为产生深远的影响,并可能导致许多神经系统疾病,包括自闭症、智力低下和精神分裂症。我们的研究结果将极大地增强我们对 3-原钙粘蛋白在神经回路组装中的功能的了解,并将为开发解决这些疾病的新治疗策略提供坚实的基础。这些研究还将有助于深入了解负责突触发生的发育机制,这对于创建有效的方法来促进脑或脊髓损伤后的修复至关重要。

项目成果

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JAMES DAVID JONTES其他文献

JAMES DAVID JONTES的其他文献

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{{ truncateString('JAMES DAVID JONTES', 18)}}的其他基金

The role of Protocadherin-17 in the development of direction selective circuits in the zebrafish visual system
Protocadherin-17 在斑马鱼视觉系统方向选择电路发育中的作用
  • 批准号:
    10582919
  • 财政年份:
    2023
  • 资助金额:
    $ 7.63万
  • 项目类别:
Protocadherin control of cell proliferation and differentiation
原钙粘蛋白控制细胞增殖和分化
  • 批准号:
    10390347
  • 财政年份:
    2021
  • 资助金额:
    $ 7.63万
  • 项目类别:
Protocadherin control of cell proliferation and differentiation
原钙粘蛋白控制细胞增殖和分化
  • 批准号:
    10799160
  • 财政年份:
    2021
  • 资助金额:
    $ 7.63万
  • 项目类别:
Protocadherin control of cell proliferation and differentiation
原钙粘蛋白控制细胞增殖和分化
  • 批准号:
    10591493
  • 财政年份:
    2021
  • 资助金额:
    $ 7.63万
  • 项目类别:
Protocadherin control of cell proliferation and differentiation
原钙粘蛋白控制细胞增殖和分化
  • 批准号:
    10185073
  • 财政年份:
    2021
  • 资助金额:
    $ 7.63万
  • 项目类别:
Protocadherins in zebrafish visual system development
原钙粘蛋白在斑马鱼视觉系统发育中的作用
  • 批准号:
    9767214
  • 财政年份:
    2016
  • 资助金额:
    $ 7.63万
  • 项目类别:
Protocadherins in zebrafish visual system development
原钙粘蛋白在斑马鱼视觉系统发育中的作用
  • 批准号:
    9159550
  • 财政年份:
    2016
  • 资助金额:
    $ 7.63万
  • 项目类别:
Mechanism of differential adhesion by protocadherin-cadherin complexes
原钙粘蛋白-钙粘蛋白复合物的差异粘附机制
  • 批准号:
    8359953
  • 财政年份:
    2012
  • 资助金额:
    $ 7.63万
  • 项目类别:
Transgenic and knockout approaches to study protocadherin function
研究原钙粘蛋白功能的转基因和敲除方法
  • 批准号:
    8430625
  • 财政年份:
    2012
  • 资助金额:
    $ 7.63万
  • 项目类别:
Mechanism of differential adhesion by protocadherin-cadherin complexes
原钙粘蛋白-钙粘蛋白复合物的差异粘附机制
  • 批准号:
    8472540
  • 财政年份:
    2012
  • 资助金额:
    $ 7.63万
  • 项目类别:

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