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，才能到达特定的位置，在那里它们形成器官和复杂的组织，如神经系统。错误的细胞迁移是许多人类疾病的根源。我们想要识别和了解参与细胞迁移的新颖的、以前未知的分子机制，以便我们能够更好地治疗或预防此类疾病。我们通过对影响模式生物(线虫)细胞迁移的基因进行突变，在显微镜下很容易跟踪细胞迁移，并使用每个突变来识别导致缺陷的基因，然后对其进行克隆和测序。由此收集的信息使我们能够确定该基因编码的产物(通常是一种与人类同源的特定蛋白质)的性质。许多蛋白质的一部分共享特定的氨基酸序列(又名结构域)，这些序列在分子水平上具有已知的功能，所以我们经常可以从感兴趣的蛋白质中存在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中推断(例如，细胞漂移或被错误定向而从未到达目的地，或未能在正确的位置停止迁移，或在到达之前停止，等等)。这种蛋白质在迁移过程中扮演什么角色，并将其与其他迁移基因突变的影响进行比较。我们最近发现了在多阶段迁移过程的特定阶段导致漂移或误导迁移的基因突变。两个这样的基因的蛋白质产物帮助在分泌的蛋白质上建立糖链，所以我们第一次开始了解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指导迁移细胞，因此我们的研究应该澄清这种调节是如何在分子水平上发生的。然而，这是一项由好奇心驱动的研究，我们希望(正如经常发生的那样)从这项研究中获得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.