Resource for marking clones on the fly 4th chromosome

用于在第四条染色体上标记克隆的资源

• 批准号: 9372952
• 负责人: STUART J NEWFELD
• 金额: $ 19.68万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9372952
• 关键词: Activins; Adult; Area; Attention; BCL9 gene; Biological; Biology; Brain; Cell Communication; Cell physiology; Cells; Chromosome Segregation; Chromosomes; Communities; Development; Disease; Distal; Drosophila genus; Drosophila melanogaster; Enteral; FOXL1 gene; Family; Funding; Future; GDF8 gene; Genes; Genetic; Genetic Recombination; Health; Human; Institutes; Intestines; Knowledge; Letters; Ligands; Light; Mammals; Maps; Memory Loss; Methods; Molecular; Monoclonal Antibody R24; Mushroom Bodies; Mutagenesis; Mutation; Mutation Analysis; National Institute of General Medical Sciences; National Institute of Neurological Disorders and Stroke; Neuraxis; Neurobiology; Neuroglia; Neurons; Oncogenes; Orthologous Gene; Pathway interactions; Physiology; Research Personnel; Resource Development; Resources; Role; SOX5 gene; Scientist; Signal Transduction; Site; Stem cells; Syndrome; System; Systems Development; Testing; Transducers; Transforming Growth Factor beta; Transgenes; Translating; United States National Institutes of Health; Work; activin B; alpha secretase; arm; autosome; fly; frontier; genetic analysis; genetic approach; inhibin B; innovation; insight; interest; loss of function mutation; mutant; nervous system disorder; relating to nervous system; response; smoothened signaling pathway; tool; virtual; ward; Activins; Adult; Area; Attention; BCL9 gene; Biological; Biology; Brain; Cell Communication; Cell physiology; Cells; Chromosome Segregation; Chromosomes; Communities; Development; Disease; Distal; Drosophila genus; Drosophila melanogaster; Enteral; FOXL1 gene; Family; Funding; Future; GDF8 gene; Genes; Genetic; Genetic Recombination; Health; Human; Institutes; Intestines; Knowledge; Letters; Ligands; Light; Mammals; Maps; Memory Loss; Methods; Molecular; Monoclonal Antibody R24; Mushroom Bodies; Mutagenesis; Mutation; Mutation Analysis; National Institute of General Medical Sciences; National Institute of Neurological Disorders and Stroke; Neuraxis; Neurobiology; Neuroglia; Neurons; Oncogenes; Orthologous Gene; Pathway interactions; Physiology; Research Personnel; Resource Development; Resources; Role; SOX5 gene; Scientist; Signal Transduction; Site; Stem cells; Syndrome; System; Systems Development; Testing; Transducers; Transforming Growth Factor beta; Transgenes; Translating; United States National Institutes of Health; Work; activin B; alpha secretase; arm; autosome; fly; frontier; genetic analysis; genetic approach; inhibin B; innovation; insight; interest; loss of function mutation; mutant; nervous system disorder; relating to nervous system; response; smoothened signaling pathway; tool; virtual; ward

Resource for marking clones on the fly 4th chromosome For over a century, studies employing Drosophila melanogaster have resulted in significant advances in our understanding of highly conserved cellular processes and signaling systems. In the area of human health, Drosophila genetics has been an effective means for identifying disease-associated genes and for providing insights into their mechanism of action. The fourth chromosome (IV) is the final frontier for genetic analysis in Drosophila. Small and devoid of recombination IV has been largely ignored. Nevertheless, the long arm of IV contains roughly 105 genes. 55% of these genes have obvious human orthologs and 67% of the human genes have a disease association. A complete understanding of multicellularity requires the genetic analysis of mutations in these genes. Somatic and germline clones are established tools for studying the functions of lethal mutations in flies. The MARCM system for tracking clones of mutant cells he has been widely employed to study central nervous system development and adult intestinal stem cells. However, MARCM is not useable on IV due to the lack of appropriate chromosomes. As a resource for the Drosophila community whose investigators are funded by virtually all of the NIH Institutes and Centers, we propose a collaborative R21 (in response to PAR-16-141) to generate the necessary chromosomes for MARCM-IV. Our two labs are currently NIH funded for studies of TGF-β signaling and have worked together previously on the role of the Sno oncogene in TGF-β signal transduction. We will employ an innovative strategy integrating molecular methods (Crisper-Cas9) with genetics (X to autosome jumping). MARCM-IV will then be tested in studies of TGF-β signaling in the mushroom body and the enteric neurons of the larval brain. The Specific Aims of this project are: Aim1 Resource Development: To create the unique fourth chromosomes necessary for MARCM-IV. Aim2 Discovery: Proof of principal studies will utilize MARCM-IV to generate marked clones for three mutant genes. These are the TGF-β ligands activin-β and myoglianin and the Smad-interacting signal transducer dCORL (fussel in Flybase). These applications of MARCM-IV will advance our knowledge of molecular mechanisms in the TGF-β pathway, neural-glial interactions and the development/function of subesophageal neurons in the brain. The results should attract the attention of others in the Drosophila community whose interests encompass genes on IV. We will provide the MARCM-IV lines to any qualified investigator and evidence of community interest is already visible in letters appended to this proposal. Given that many of the genes on IV are conserved, new insights from MARCM-IV in flies can be readily translated into new hypotheses for normal development/physiology or diseases in humans. Looking ahead, it is likely our innovative approach can easily be expanded to an analysis of all genes on IV. The valuable community resource created by this project will be made freely available to all qualified researchers to facilitate our understanding of conserved features of developmental signaling and neurobiology impacting human health and disease.

在四染色体上标记克隆的资源 一个多世纪以来，采用果蝇的研究取得了重大进展 了解高度保守的细胞过程和信号系统。在人类健康领域， 果蝇遗传学一直是鉴定疾病相关基因并提供的有效手段 洞悉其行动机制。第四染色体（IV）是用于遗传分析的最终边界 果蝇。小而没有重组的IV已在很大程度上被忽略了。然而，IV的长臂 大约包含105个基因。这些基因中有55％具有明显的人类直系同源物和67％的人类基因 有疾病关联。对多细胞性的完整理解需要对 这些基因中的突变。体细胞和种系克隆是建立了研究的工具 苍蝇中的致命突变。 MARCM跟踪突变细胞克隆的系统已被广泛使用 研究中枢神经系统发育和成年肠干细胞。但是，Marcm不可用 由于缺乏适当的染色体，因此在IV上。作为果蝇社区的资源 调查人员几乎由所有NIH机构和中心资助，我们提出合作R21（在 对PAR-16-141的响应，以生成MARCM-IV的必要染色体。我们的两个实验室目前是 NIH资助用于TGF-β信号的研究，并以前曾在SNO的作用 TGF-β信号转移中的癌基因。我们将采用整合分子方法的创新策略 （Crisper-Cas9）带有遗传学（X到自染色体跳跃）。然后将在TGF-β的研究中测试MARCM-IV 肌肉体和进入幼虫大脑的神经元的信号传导。该项目的具体目的 为：AIM1资源开发：创建MARCM-IV所需的独特的第四个染色体。 AIM2 发现：主要研究证明将利用MARCM-IV来生成三个突变基因的明显克隆。 这些是TGF-β配体激活素-β和肌lianin以及Smad相互作用信号传感器dcorl （在飞箱中的富瑟）。 MARCM-IV的这些应用将提高我们对分子机制的了解 TGF-β途径，神经胶质相互作用和亚菌根神经元的发展/功能 脑。结果应吸引果蝇社区中他人的注意力 包含IV上的基因。我们将向任何合格的调查员提供MARCM-IV线路，并证明 社区兴趣已经在附加到该提案的信件中可以看到。鉴于IV上的许多基因 如果保守，可以将Marcm-IV的新见解轻易转化为正常的新假设 人类的发展/生理或疾病。展望未来，我们的创新方法很可能很容易 扩展到对IV上所有基因的分析。该项目创建的价值社区资源将是 向所有合格的研究人员免费提供，以促进我们对 发育信号传导和神经生物学影响人类健康和疾病。