A genetic approach to discover novel regulators of microtubule behaviour

我们研究的目标是了解有丝分裂纺锤体等微观结构如何在活细胞中组装。 像大多数复杂的4维生物过程一样，对纺锤体组装的完整理解将取决于对单个组件特性的了解，以及对它们在活细胞中如何组装的理解。 我们使用线虫秀丽隐杆线虫来研究这个问题，因为微管结构在第一次细胞分裂中迅速组装和分解，并且可能需要许多调节分子来提供指令。 微管对细胞分裂的重要性，以及它们对这种分子指令的敏感性，可能最好地证明了许多抗癌药物靶向微管聚合物（例如紫杉醇和长春碱）的事实。 然而，我们没有一个完整的了解微管的生长和拆卸是如何在细胞内调节。 通过使用抑制遗传学和RNA介导的干扰相结合，我们将寻找在C.优雅 这将通过侧重于两种不同的监管途径来实现。 第一个涉及中心体（细胞中大多数微管的核结构）蛋白磷酸化的调节。 我们希望能够识别出那些执行信号指令的蛋白质，这些信号指令微管“构建有丝分裂纺锤体”。 第二个项目将侧重于鉴定一个基因，由于其突变表型，可能需要在早期受精卵准备第一次有丝分裂时协调微管行为。 总之，这些途径提供了一个理想的起点，发现新的微管动力学调节剂，并可能进一步加深我们对高等真核生物细胞分裂的理解。

The goal of our research is to understand how microscopic structures such as the mitotic spindle assemble in living cells.  Like most complex 4-dimensional biological processes, a complete understanding of spindle assembly will depend on knowledge of the properties of individual components as well as an appreciation for how their assembly is orchestrated in living cells.  We use the nematode Caenorhabditis elegans to study this problem because microtubule structures are assembled and disassembled rapidly in the first cell division, and many regulatory molecules are likely required to provide the instructions.  The importance of microtubules to cell division, and their sensitivity to such molecular instruction, is perhaps best evidenced by the fact that many anti-cancer drugs target the microtubule polymer (e.g. Taxol and Vinblastine).  However, we do not have a complete understanding of how microtubule growth and disassembly is regulated within the cell.  By using a combination of suppressor genetics and RNA-mediated interference, we will search for genes that are required for microtubule processes in the first cell division of C. elegans.  This will be accomplished by focusing on two distinct pathways of regulation.  The first involves the regulation of protein phosphorylation at the centrosome (a structure that nucleates the majority of microtubules in the cell).  We hope to identify proteins that are carrying out the orders of a signal that instructs microtubules to "build a mitotic spindle".  The second project will focus on the identification of a gene that, because of its mutant phenotype, is likely required to coordinate microtubule behaviour at a time when the early fertilized egg prepares for the first mitotic division.  Together, these pathways provide an ideal starting point to discover novel regulators of microtubule dynamics and will likely further our understanding of cell division in higher eukaryotes.