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

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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.