The role of ARL13B in controlling ciliary cAMP signaling

• Applicants: Professor Dr. David Mick; Professorin Dr. Dagmar Wachten
• Subject Area: Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513767027

Cellular communication is crucial for cell differentiation, tissue development and function. Chemical and protein cues are key signaling molecules for cell communication and a slender protrusion from the surface of the cell body, called the primary cilium, acts as a cellular antenna that receives extracellular cues and transduces this information into the cell body. The biggest challenge in understanding how cilia receive signals from the environment is that the small cilium is challenging to functionally or physically isolate. In turn, distinguishing what is happening within the cilium versus the cell body is murky. Genetic ablation of cilia abolishes all ciliary signaling, making it impossible to dissect ciliary-specific signaling pathways. Cyclic AMP (cAMP) is a central messenger for ciliary signaling. However, how the cell distinguishes between ciliary and cytoplasmic cAMP signaling outputs and which signaling pathways and cellular cues are specifically engaged by ciliary cAMP signaling is not known. The Wachten and Mick labs have recently shown that chronic stimulation of ciliary cAMP signaling controls epithelial cell remodeling. Recent data from the Caspary lab indicates that loss of ciliary ARL13B, by introducing a mutation that inhibits transport of ARL13B to the cilium, shows striking similarities to chronic ciliary cAMP stimulation. Here, we hypothesize that ARL13B in the cilium defines the ciliary cAMP compartment and that loss of ARL13B in the cilium increases ciliary cAMP levels that, in turn, changes epithelial cell polarity and morphology. To test this hypothesis, we will apply genetically-encoded biosensors and optogenetic tools in genetically modified, renal epithelial cells lacking ciliary ARL13B and combine this approach with spatial proteomics in the cilium to unravel how ARL13B controls ciliary cAMP signaling and epithelial cell remodeling. The outcome of our work will contribute to the understanding of how compartmentalized signaling in primary cilia controls cellular signaling and function.

• DFG Programme: Research Grants
• International Connection: USA
• Partner Organisation: National Science Foundation (NSF)
• Cooperation Partner: Professorin Dr. Tamara Caspary