Post-transcriptional mechanisms of centrosome regulation

项目摘要 中心体失调是遗传性小头畸形的主要原因， 与智力残疾和发育迟缓有关。中心体功能障碍也被认为是 癌症的关键驱动因素和预后标志物。然而，中心体调控的机制仍然存在， 不完全理解。中心体在组成和组织上经历细胞周期依赖性变化 调节它们作为微管组织中心的活动，这些振荡有助于细胞的多样性。 中心体功能中心体的一个动态成分是mRNA，但mRNA的功能作用 定位于中心体的机制仍知之甚少。在这个建议中，我们研究mRNA是否有助于 中心体的调节和功能。在目标1中，我们定义了mRNA定位的机制， 中心体在目标2中，我们发现了两个保守的RNA结合蛋白的调节作用。目标3 检查位于中心体的mRNA的功能。这项工作的完成将解决长期- 在一个遗传学上易处理的模型中，mRNA定位于中心体的作用是一个悬而未决的问题。这 这项工作将有助于我们理解中心体调节，在某些情况下， 小头畸形和癌症。

Project Summary Centrosome deregulation is the leading cause of heritable microcephaly, a congenital birth defect typically associated with intellectual disabilities and developmental delay. Centrosome dysfunction is also considered a key driver and prognostic marker of cancer. Yet, mechanisms underlying centrosome regulation remain incompletely understood. Centrosomes undergo cell cycle-dependent changes in composition and organization to modulate their activity as microtubule-organizing centers, and these oscillations contribute to the diversity of centrosome functions. One dynamic constituent of centrosomes is mRNA, yet the functional role of mRNA localized to centrosomes remains poorly understood. In this proposal, we examine whether mRNA contributes to centrosome regulation and functions. In Aim 1, we define mechanisms of mRNA localization to centrosomes. In Aim 2, we uncover the regulatory contributions of two conserved RNA-binding proteins. Aim 3 examines the function of mRNA localized to centrosomes. The completion of this work will address long- standing questions about the role of mRNA localized to centrosomes within a genetically tractable model. This work will contribute to our understanding of centrosome regulation, aspects of which are deregulated in cases of microcephaly and cancer.