Coordination Funds

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How cells assemble into tissues and maintain tissue integrity are central questions in biology. Primary cilia project from the surface of most vertebrate cells, where they sense and locally transduce extracellular signals. Primary cilia do not function as static organelles. Instead, they dynamically integrate extracellular input, thereby controlling cell fates and functions during tissue development, maintenance, and remodeling in disease. Primary cilia function relies on i) the dynamic composition of molecules within the cilium, precisely regulated by the ciliary trafficking machinery and gating at the ciliary base, ii) the context-dependent sensing and processing of extracellular stimuli, and iii) the dynamic assembly and disassembly in a cell- and tissue-specific manner. We hypothesize that integrating this triad of primary cilia dynamics is critical to control cellular processes during tissue organization and function. Dissecting how primary cilia dynamics govern tissue organization cannot be addressed by an individual lab but requires a collaborative research effort in a Research Unit (RU) with combined expertise covering ciliary dynamics in different tissue types. Thus, the RU will address the common goal in a joint effort, which goes beyond what could be achieved by individual projects or investigators. Our RU consists of seven projects (P1 to P7). P1, P2, and P3 will define how the dynamics of intraciliary molecules control cell fate, morphogenesis, and tissue organization. P4 and P5 will reveal how extracellular stimuli regulate primary cilia dynamics to control cell fate and function. Finally, P6 and P7 will identify the molecular mechanisms underlying how primary cilia assembly/disassembly dynamics and the changes in ciliary signaling dynamics regulate tissue organization. Importantly, every project covers at least two levels of cilia dynamics, uses 2D cell culture and 3D organoids or in vivo animal models, and employs high-content data and specific hypotheses to gain mechanistic understanding. The RU will also include a Mercator fellow who will provide standardized technological and quantitative procedures to analyze cilia dynamics using imaging. Our common goal is to analyze cilia dynamics across different cells and tissues and uncover common and context-specific mechanisms that regulate tissue development and function. On the long term, our combined efforts will allow to decipher the mechanisms that impair cilia dynamics in ciliopathies, and identify potential therapeutic targets.