Mapping the CPLANE interactome, an extensive protein interaction network underlying human ciliopathies

摘要 纤毛是必需的细胞器，其功能从细胞间信号传递到产生内环境平衡。 管状器官中的液体流动。因此，一系列人类先天性疾病被描述为 “纤毛病症”，因为它们都有纤毛结构或功能缺陷的病因。尽管有明显的角色 中枢神经系统、四肢、中轴骨、肾脏、呼吸道、大脑和生殖系统的破坏 纤维束，我们对纤毛发生和纤毛介导的发育机制的理解 阵列仍未完成。我们建议在这里研究一种新的多蛋白复合体的作用 控制三个关键机制：基础身体对接、鞭毛内运输(IFT)招募和平面 细胞极性(PCP)。我们将结合蛋白质组学、体内细胞生物学、小鼠遗传学和 人类疾病模型。通过重点研究在发育和疾病中具有重要意义的蛋白质， 但对于其作用机制尚不清楚，这里提出的实验将提供重要的新 广度和深度来理解纤毛介导的发育模式，基础身体对接，以及 纤毛生物学中的新细胞生物学过程。反过来，这些发现应该会为一系列研究提供更深入的见解 先天疾病，包括相对轻微的口腔-面部-指端综合征和完全致命的 短肋骨多指。

ABSTRACT Cilia are essential organelles, with functions ranging from cell-cell signaling to the generation of homeostatic fluid flow in tubular organs. Consequently, an array of human congenital diseases has been characterized as “ciliopathies,” because they share an etiology of defective cilia structure or function. Despite manifest roles in the disruption of the central nervous system, limbs, axial skeleton, kidneys, airway, brain, and reproductive tracts, our understanding of the mechanisms that govern ciliogenesis and cilia-mediated developmental patterning remain incomplete. We propose here to study the roles of a novel multi-protein complex that controls three crucial mechanisms: basal body docking, IntraFlagellar Transport (IFT) recruitment, and Planar Cell Polarity (PCP). We will do so using a combination of proteomics, in vivo cell biology, mouse genetics and human disease modeling. By focusing on proteins with demonstrated importance in development and disease, but for which no mechanism of action is yet known, experiments proposed here will provide important new breadth and depth to our understanding cilia-mediated developmental patterning, basal body docking, and novel cell biological processes in ciliary biology. In turn, these findings should provide greater insight to a range of congenital diseases including both the relatively mild Oral-Facial-Digital syndrome and the wholly lethal Short Rib Polydactyly.