Extracellular Matrix and Axonal Guidance in C. elegans

描述（由申请人提供）：神经系统包括纵向和周向神经的网格状网络。已经发现几种分子引导C.包括netrin蛋白家族的创始成员β-6。然而，很少有人知道，关于管理不同的反应个别迁移轴突对这些指导线索的分子机制。这些差异很重要，因为它们允许各种轴突迁移模式的发展和更多数量的连接形成。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，基因正在被识别和研究，影响的指导只有子集的圆周迁移轴突。具体而言，这些基因是所需的迁移模式，是不同于其他圆周轴突。在一种情况下，已经发现一种基因仅在少数神经元中表达，并且编码保守的细胞质蛋白。该基因在遗传上与编码已知轴突引导信号通路的组分的基因相互作用，因此是调节神经元特异性轴突引导反应的强有力的候选者。 第二，基因筛选被用来分离第二个位点突变，抑制特定unc-6突变的表型。这些unc-6突变破坏了负责介导不同的β-6指导活性的β-6结构域。通过分离可以抑制这些unc-6突变的表型的突变，可以鉴定与nc-6相互作用以帮助介导不同nc-6活性的蛋白质。在初步筛选中，一个基因外突变恢复了unc-6突变引起的不协调运动和轴突导向缺陷。 了解控制轴突和细胞导向的分子机制对于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.