Extracellular Matrix and Axonal Guidance in C. elegans

线虫的细胞外基质和轴突引导

• 批准号: 7416580
• 负责人: WILLIAM G WADSWORTH
• 金额: $ 33.61万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7416580
• 关键词: Affect; Alleles; Axon; Biological Assay; Caenorhabditis elegans; Cell Surface Receptors; Cells; Coupling; Cues; Cytoplasmic Protein; DNA Sequence Alteration; Defect; Development; Disease; Dorsal; Extracellular Matrix; Genes; Genetic; Genetic Screening; Immigration; Individual; Injury; Ligands; Maps; Mediating; Molecular; Morphology; Movement; Mutation; Nerve; Nervous system structure; Neurons; Numbers; Pattern; Phenotype; Play; Protein Family; Proteins; Receptor Gene; Research; Research Personnel; Role; Signal Pathway; Site; Suppressor Mutations; System; Temperature; Therapeutic Agents; Transcript; axon guidance; axonal guidance; base; extracellular; loss of function; member; migration; mutant; receptor; response; scale up; Affect; Alleles; Axon; Biological Assay; Caenorhabditis elegans; Cell Surface Receptors; Cells; Coupling; Cues; Cytoplasmic Protein; DNA Sequence Alteration; Defect; Development; Disease; Dorsal; Extracellular Matrix; Genes; Genetic; Genetic Screening; Immigration; Individual; Injury; Ligands; Maps; Mediating; Molecular; Morphology; Movement; Mutation; Nerve; Nervous system structure; Neurons; Numbers; Pattern; Phenotype; Play; Protein Family; Proteins; Receptor Gene; Research; Research Personnel; Role; Signal Pathway; Site; Suppressor Mutations; System; Temperature; Therapeutic Agents; Transcript; axon guidance; axonal guidance; base; extracellular; loss of function; member; migration; mutant; receptor; response; scale up

DESCRIPTION (provided by applicant): Nervous systems comprise a grid-like network of longitudinal and circumferential nerves. Several molecules have been found that guide circumferential migrations in C. elegans including UNC-6, the founding member of the netrin protein family. Little is known, however, about the molecular mechanisms that govern different responses individual migrating axons have to these guidance cues. These differences are important since they allow a variety of axon migration patterns to develop and a greater number of connections to form. Two approaches are proposed to study the molecular basis of the responses that axons have to guidance cues. First, genes are being identified and studied that affect the guidance of only subsets of circumferentially migrating axons. Specifically, these genes are required for migration patterns that are different from those of other circumferential axons. In one case, a gene has been found that is expressed in only a few neurons and which encodes a conserved cytoplasmic protein. This gene genetically interacts with genes encoding components of known axon guidance signaling pathways and is therefore a strong candidate for regulating neuron-specific axon guidance responses. Second, genetic screens are being used to isolate second site mutations that suppress the phenotypes of specific unc-6 mutations. These unc-6 mutations disrupt UNC-6 structural domains that are responsible for mediating distinct UNC-6 guidance activities. By isolating mutations that can suppress the phenotypes of these unc-6 mutations, proteins that interact with UNC-6 to help mediate the different UNC-6 activities might be identified. In a pilot screen, an extragenic mutation that reverts the uncoordinated movement and axon guidance defects caused by an unc-6 mutation has been recovered. Understanding the molecular mechanisms that control axon and cell guidance could prove critical for developing therapeutic agents that treat nerves damaged by injuries or disease.

描述（由申请人提供）：神经系统包括一个类似网格的纵向和圆周神经网络。已经发现几个分子可以指导秀丽隐杆线虫中的圆周迁移，其中包括Netrin蛋白家族的创始成员UNC-6。然而，关于控制单个迁移轴突对这些指导提示的不同反应的分子机制知之甚少。这些差异很重要，因为它们允许发展各种轴突迁移模式，并形成更多的连接。提出了两种方法来研究轴突对引导提示的反应的分子基础。 首先，正在鉴定和研究基因，这些基因仅影响圆周迁移轴突的子集的引导。具体而言，这些基因是与其他圆周轴突不同的迁移模式所必需的。在一种情况下，已经发现一个基因仅在几个神经元中表达，并且编码保守的细胞质蛋白。该基因与编码已知轴突引导信号通路成分的基因相互作用，因此是调节神经元特异性轴突引导反应的有力候选者。 其次，遗传筛选用于分离抑制特定UNC-6突变表型的第二位点突变。这些UNC-6突变破坏了导致介导不同的UNC-6指导活动的UNC-6结构域。通过隔离可以抑制这些UNC-6突变的表型的突变，可以鉴定出与UNC-6相互作用以帮助介导不同的UNC-6活性的蛋白质。在试点屏幕中，恢复了由UNC-6突变引起的不协调运动和轴突引导缺陷的外部突变。 了解控制轴突和细胞引导的分子机制对于开发治疗受伤或疾病损害的神经的治疗剂至关重要。