In Caenorhabditis elegans, loss of ciliary Gα ODR-3 reduces cilia complexity in a subset of olfactory neurons. For example, overexpression of the ciliary GPCR 5-HT6, which binds the neurotransmitter serotonin, induces the formation of excessively long cilia in cortical neurons. Notably, many GPCRs and their downstream effectors localize to cilia in different cell types including neurons and can modulate cilia morphology. Heterotrimeric G (αβγ) proteins are canonical transducers of G protein coupled receptor (GPCR) signaling. As a result, defects in cilia structure or function manifest in a spectrum of human genetic disorders called ciliopathies, many of which are associated with neurological deficits.
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Cilia in different eukaryotic species concentrate molecular machinery of key signaling pathways, which in turn require intact cilia for proper transduction. Their core organization and assembly mechanisms are highly conserved across evolution. Primary cilia are hair-like cellular compartments that protrude from the surface of nearly all metazoan cell types. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. Hood Foundation Child Health Research Award (IN ).
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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the manuscript and its Supporting Information files.įunding: This work was supported by the National Institute of Child Health and Human Development (R15 HD109706, IN ) and Charles H. Received: AugAccepted: OctoPublished: November 1, 2023Ĭopyright: © 2023 Campagna et al. Dutcher, Washington University School of Medicine, UNITED STATES
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Collectively, our findings describe a novel function for the evolutionarily conserved protein RIC-8 and non-canonical RIC-8-AGS-3-ODR-3 signaling in cilia morphogenesis and uncouple Gα ODR-3 functions in ciliogenesis and olfaction.Ĭitation: Campagna CM, McMahon H, Nechipurenko I (2023) The G protein alpha chaperone and guanine-nucleotide exchange factor RIC-8 regulates cilia morphogenesis in Caenorhabditis elegans sensory neurons. Notably, despite defects in AWC cilia morphology, ags-3 null mutants exhibit normal chemotaxis toward benzaldehyde unlike odr-3 mutant animals. We identify ODR-3 as the RIC-8 Gα client and demonstrate that RIC-8 functions in the same genetic pathway with another component of the non-canonical G protein signaling AGS-3 to shape cilia morphology. Using domain mutagenesis, we demonstrate that while the GEF function alone is not sufficient, both the GEF and Gα-interacting chaperone motifs of RIC-8 are required for its role in cilia morphogenesis. elegans RIC-8 localizes to cilia in different sensory neuron types. Consistent with its role in ciliogenesis, C. Here, we show that RIC-8, a cytosolic guanine nucleotide exchange factor (GEF) and chaperone for Gα protein subunits, shapes cilia membrane morphology in a subset of Caenorhabditis elegans sensory neurons.
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Many GPCRs and heterotrimeric G proteins localize to primary cilia and modulate cilia morphology via mechanisms that are not well understood. Heterotrimeric G (αβγ) proteins are canonical transducers of G-protein-coupled receptor (GPCR) signaling and play critical roles in communication between cells and their environment.