Novel molecular mechanisms of cell migration in C. elegans

在动物发育过程中，许多细胞必须向特定的方向迁移，到达特定的位置，在那里它们形成器官和复杂的组织，如神经系统。有缺陷的细胞迁移是许多人类疾病的基础。我们想要识别和理解新的、以前未知的与细胞迁移有关的分子机制，这样我们就可以更好地治疗或预防这种疾病。我们通过在影响模型生物（秀丽隐杆线虫）细胞迁移的基因中制造突变来做到这一点，在这种模式生物中，细胞迁移很容易在显微镜下跟踪，并使用每个突变来识别导致缺陷的基因，然后我们对其进行克隆和测序。从中收集的信息使我们能够确定由该基因编码的产物（通常是具有人类同源物的特定蛋白质）的性质。许多蛋白质的某些部分共享特定的氨基酸序列（又称结构域），这些氨基酸序列在分子水平上具有已知的功能，因此我们经常可以从感兴趣的蛋白质中存在的这些结构域来判断该蛋白质是如何工作的。我们还可以从突变体中细胞迁移缺陷的类型推断出（例如，细胞漫游或被误导，从未到达目的地，或未能在正确的位置停止迁移，或在到达目的地之前停止迁移，等等）该蛋白质在迁移过程中起什么作用，并将其与其他迁移基因突变的影响进行比较。我们最近发现，在多阶段迁移过程的特定阶段，基因突变会导致流浪或错误的迁移。这两个基因的蛋白质产物帮助在分泌的蛋白质上构建糖链，因此我们第一次开始了解这些特定蛋白质上的糖链如何影响细胞迁移。另一个基因调节一个先前已知的关键基因，该基因在发育中的人类中枢神经系统中起引导迁移细胞的作用，因此我们的研究应该阐明这种调节是如何在分子水平上发生的。这是一项好奇心驱动的研究，然而，我们希望（正如经常发生的那样）从这项研究中收集到的知识最终将适用于理解和治疗几种人类发育障碍以及转移性癌症中发生的细胞异常迁移。

During animal development, many cells must migrate in specific directions to reach specific locations where they form organs and complex tissues like the nervous system. Faulty cell migrations underlie many human disorders. We want to identify and understand novel, previously unknown molecular mechanisms involved in cell migration so we can better treat or prevent such disorders. We do this by making mutations in genes that affect cell migration of a model organism (C. elegans) in which cell migrations are easily followed microscopically and using each mutation to identify the gene responsible for the defect, which we then then clone and sequence. The information gleaned from this allows us to determine the nature of the product (usually a specific protein with human homologs) encoded by the gene. Portions of many proteins share specific amino acid sequences (aka domains) that have known functions at a molecular level, so often we can tell from the presence of such domains in a protein of interest, how that protein works. We can also deduce from the kind of cell migrations defect in the mutant (e.g. the cell wanders or is misdirected and never reaches its destination, or it fails to stop migrating in the correct place, or stops before reaching it, etc.) what role that protein plays in the migration process and compare this to the effects of mutations in other migration genes. We have recently identified mutations in genes that cause wandering or misdirected migrations at a specific stage of a multi-stage migration process. The protein products of two such genes help build sugar chains on secreted proteins, so we are beginning for the first time to understand how these sugar chains on specific proteins affect cell migration. Another gene modulates a previously known key gene that functions to guide migrating cells in the developing human central nervous system, so our studies should clarify how this modulation occurs at a molecular level. This is curiosity driven research, however, we hope (as often happens) that the knowledge gleaned from this research will eventually be applicable to understanding and treating several human developmental disorders as well as the abnormal migration of cells that occurs in metastatic cancer.