Signaling proteins are often sequestered into cellular domains, where different modulator proteins, and potentially lipid environments, ensure efficient signal transduction. How such domains form represents an important, largely unexplored question. Known as the antennae of the cell, cilia are organelles required for many signaling pathways, presenting an unique opportunity to explore how signal transduction is arranged spatially and regulated dynamically in the cells. Using the AFD thermosensory neurons of C. elegans as the model system, my research investigated the roles of ciliary proteins in regulating a signaling cascade closely associated with the cilium – the cGMP signaling pathway. I showed that different functional categories of ciliary proteins help establish two contiguous, yet distinct cGMP signaling compartments in the sensory end of AFD neurons. One compartment, a bona fide cilium, is delineated by Bardet-Biedl syndrome (BBS), Meckel syndrome (MKS) and nephronophthisis (NPHP) associated proteins at its base, and requires Inversin/NPHP-2 to anchor a cGMP-gated ion channel within the proximal ciliary region. The other, a subcompartment characterized by profuse microvilli and different lipid environment, is separated from the dendrite by a cellular junction and requires BBS-8 and DAF-25/Ankmy2 for correct localization of guanylyl cyclases needed for thermosensation. Consistent with a requirement for a membrane diffusion barrier at the subcompartment base, my data revealed the unexpected presence of ciliary transition zone proteins where no canonical transition zone ultrastructure (Y-links) is observed. My results also showed that the ciliary mutants have a reduced ability in moving toward favorable temperatures, a behavior known as thermotaxis. Finally, using a novel conditional knockout method developed during this research, I showed that the cilium acts cell-autonomously for the function of AFD neurons in thermotaxis. Based on the similarities with mammalian photoreceptors, my research suggests that differential compartmentalization of signal transduction components using different classes of ciliary proteins is important for the functions of ciliated sensory neurons.
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Thesis advisor: Leroux, Michel R.
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