Structure and mechanism of the centrosome-cilium complex

摘要 中心体-纤毛复合体是动物细胞功能的重要细胞器。中心体是 动物细胞的主要微管组织中心，中心体内的中心粒 具有独特的结构，允许它们充当纤毛组装的引发剂。 初级纤毛是小的，触角状的细胞器，对脊椎动物的发育和 生理学。中心体-纤毛复合体缺陷导致人类疾病，称为 纤毛病，以广泛的表型为特征，突出了它们在 多种细胞类型和器官。这个复合体形成了细胞的一个不同的隔间，有一个 高度极化的微管细胞骨架引导细胞内的流量往返于它，以及一个 质膜周围部分质膜的特化节段。在大多数单元格中，只有 一个中心体-纤毛复合体，但这种复合体经常在一系列疾病的细胞中改变，并且 在有特定发育程序以放大中心粒的细胞中。纤毛的功能 关键取决于蛋白质组成和定位的动态变化。特别是， Hedgehog(HH)信号转导，对胚胎发育和成体组织至关重要 再生和癌症，主要发生在初级纤毛，并涉及运动 作为对信号的反应，信号蛋白进入和离开纤毛。我们已经定义了六个 推动这项拟议研究的基本问题。 1)中心粒的特化复合微管是如何形成的，它们是如何形成的 是否只在中心粒形成？ 2)中心粒如何功能化以实现纤毛形成的基本作用； 中心体形成，复制？ 3)未能保持中心粒数量的后果是什么？ 是否存在有助于恢复正常状态的机制？ 4)在特定的分化环境中，哪些机制促进中心粒的扩增和丢失？ 5)纤毛中的信号蛋白在单分子水平上的行为是什么，以及如何 它会随着通路的激活而改变吗？ 6)纤毛是如何分解的，相同的机构在不同的环境中使用 跨越进化论？ 我们将结合使用先进的成像、细胞培养和体外分化模型， 结合先进的分子生物学来解决这些问题。成功 这些实验的结果将有助于我们对中心体纤毛缺陷的理解 疾病状态，包括纤毛疾病和癌症，并可能导致新的治疗方法 接近了。 好了！

Abstract The centrosome-cilium complex is a critical organelle of animal cell function. The centrosome is the main microtubule organizing center of animal cells, and the centrioles within the centrosome have a unique structure that allows them to serve as initiators of the assembly of a cilium. Primary cilia are small, antenna-like organelles critical for vertebrate development and physiology. Defects in the centrosome-cilium complex result in human diseases called ciliopathies, characterized by a wide spectrum of phenotypes, highlighting their important role in multiple cell types and organs. This complex forms a distinct compartment of the cell, with a highly polarized microtubule cytoskeleton directing intracellular traffic to and from it, and a specialized segment of the plasma membrane surrounding part of it. In most cells, there is only one centrosome-cilium complex, but this is often altered in cells from a range of diseases, and in cells that have specific developmental programs to amplify centrioles. The function of cilia critically depends on the dynamic changes in protein composition and localization. In particular, Hedgehog (Hh) signaling transduction, essential for embryonic development, adult tissue regeneration and cancer, largely takes place at primary cilia, and involves movements of the signaling proteins into and out of the cilium in response to signal. We have defined six fundamental questions that drive the proposed research. 1) How do the specialized compound microtubules of centriole form, and how do they specifically form only at the centriole? 2) How are centrioles functionalized to carry out the essential roles of cilium formation, centrosome formation, duplication? 3) What are the consequences of failure to maintain centriole number, and what homeostatic mechanisms exist that could facilitate a return to the normal state? 4) What mechanisms promote centriole amplification and loss in specific differentiated contexts? 5) What is the behavior of signaling proteins in the cilium, at the single molecule level, and how does it change in response to activation of the pathway? 6) How are cilia disassembled and is the same mechanism used in different contexts and across evolution? We will use a combination of advanced imaging, cell culture and in vitro differentiation models, combined with sophisticated molecular biology to address these questions. Successful outcomes in these experiments will inform our understanding of centrosome-cilium defects in disease states, including ciliopathies and cancer, and potentially lead to new therapeutic approaches. !