Is Calcium everything? The role of Ca2+ and G-protein coupled receptors in cilia signaling

初级纤毛是所有哺乳动物细胞表面的孤立的、不活动的、触角状的结构。纤毛通过其广泛的丰度和大量的纤毛特异性离子通道和受体，在细胞信号和细胞通讯中具有重要的功能。纤毛信号转导的缺陷会产生很大的影响，并可能导致多种疾病，称为纤毛疾病。这些疾病从先天性心脏病到多囊肾病，再到中枢神经系统疾病。它们中的许多起源于胚胎发育，如先天性心脏病。最近的研究表明，纤毛信号在胚胎发育过程中左右不对称的形成中起着至关重要的作用。发育过程中不对称轴的失调可能导致整个器官系统的不正确表达，并导致几种疾病的发展，如先天性心脏病。纤毛检测到哪些信号以及纤毛是如何传递这些信号的，目前尚不清楚。主办方的研究小组可以推翻机械信号转导的主要假说，将化学感觉假说，即配体介导的信号转导，保留在当前研究的重点。本项目研究初生纤毛在左右不对称胚胎发育中的基础作用，特别关注纤毛G蛋白偶联受体和纤毛钙信号转导。该项目使用胚胎节点作为纤毛信号的模型系统。首次对结节不同细胞类型的转录组进行了分析，以了解潜在的配体和受体的表达，这些配体和受体可以传递或检测不对称中介信号。利用化学遗传学和光遗传学工具来操纵初级纤毛中不同的信号通路，以揭示纤毛信号通路对已知不对称因子基因表达的影响。这些初级纤毛信号转导通路的阐明，对于了解初级纤毛在上述细胞和组织中的基本功能以及今后纤毛疾病的治疗具有重要意义。

Primary cilia are solitary, non-motile, antenna-like structures on the surface of all mammalian cells. Cilia have important functions in cellular signaling and cell communication through their ubiquitary abundance and the high number of cilia-specific ion channels and receptors. Defective ciliary signal transduction has a large impact and can lead to a variety of disease, called ciliopathies. These diseases range from congenital heart disease to polycystic kidney disease to disorder of the central nervous system. Many of them originate in the embryonic development, like congenital heart disease. Recent studies point to a crucial role of cilia signaling in the formation of the left-right asymmetry during embryonic development. The dysregulation of the asymmetric axis during the development can lead to an incorrect expression of the whole organ system and contribute to the development of several disease like congenital heart disease. It is unknown which signals are detected by cilia and how these signals are transmitted by the cilium. The hosting research group could confound the predominant hypothesis stating a mechanical signal transduction, leaving the chemosensoric hypothesis, i.e. a ligand-mediated signal transduction, in the focus of current research. The current project investigates the fundamental role of primary cilia in embryonic development of left-right asymmetry with special focus on ciliary G-protein coupled receptors and ciliary Ca2+-signaling. The project uses the embryonic node as a model system for ciliary signaling. For the first time the transcriptome of the different cell types of the node are analyzed regarding the expression of potential ligands and receptors which could transmit or detect an asymmetry-mediating signal. Chemogenetic and optogenetic tools are employed to manipulate different signaling pathways in primary cilia to reveal the impact of ciliary signaling pathways on the gene expression of known asymmetry factors. The elucidation of these fundamental signaling pathways in primary cilia is crucial to understand the basic function of primary cilia in the above described cells and tissues and to improve the therapy of ciliopathies in the future.