Extracellular Matrix and Axonal Guidance in C. elegans

描述(申请人提供)：神经系统由纵向和周向神经组成的网格状网络。已经发现了几种引导线虫周向迁移的分子，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引导线索的不同反应的分子机制，人们知之甚少。这些差异很重要，因为它们允许形成各种轴突迁移模式和形成更多数量的连接。提出了两种方法来研究轴突对引导线索的反应的分子基础。 首先，正在识别和研究的基因只影响周向迁移轴突的子集的引导。具体地说，这些基因是不同于其他环状轴突的迁移模式所必需的。在一个案例中，发现了一种只在少数神经元中表达的基因，它编码一种保守的细胞质蛋白。该基因与已知轴突引导信号通路的编码基因相互作用，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，基因筛查正被用于分离抑制特定UNC-6突变表型的第二位点突变。这些UNC-6突变破坏了UNC-6结构域，这些结构域负责调节不同的UNC-6指导活动。通过分离可以抑制这些UNC-6突变表型的突变，可以识别与UNC-6相互作用的蛋白质，以帮助调节不同的UNC-6活性。在飞行员的筛查中，修复了由UNC-6突变引起的不协调运动和轴突引导缺陷的基因外突变已经恢复。 了解控制轴突和细胞引导的分子机制可能被证明对开发治疗因损伤或疾病而受损的神经的治疗剂至关重要。

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.