title: G-protein-coupled receptors and localized signaling in the primary cilium during ventral neural tube patterning.
abstract: The primary cilium is critical in sonic hedgehog (Shh)-dependent ventral patterning of the vertebrate neural tube. Most mutants that cause disruption of the cilium result in decreased Shh signaling in the neural tube. In contrast, mutations in the intraflagellar complex A (IFT-A) and the tubby family protein, Tulp3, result in increased Shh signaling in the neural tube. Proteomic analysis of Tulp3-binding proteins first pointed to the role of the IFT-A complex in trafficking Tulp3 into the cilia. Tulp3 directs trafficking of rhodopsin family G-protein-coupled receptors (GPCRs) to the cilia, suggesting the role of a GPCR in mediating the paradoxical effects of the Tulp3/IFT-A complex in causing increased Shh signaling. Gpr161 has recently been identified as a Tulp3/IFT-A-regulated GPCR that localizes to the primary cilium. A null knock-out mouse model of Gpr161 phenocopies Tulp3 and IFT-A mutants, and causes increased Shh signaling throughout the neural tube. In the absence of Shh, the bifunctional Gli transcription factors are proteolytically processed into repressor forms in a protein kinase A (PKA) -dependent and cilium-dependent manner. Gpr161 activity results in increased cAMP levels in a Gαs -coupled manner, and determines processing of Gli3. Shh signaling also results in removal of Gpr161 from the cilia, suggesting that Gpr161 functions in a positive feedback loop in the Shh pathway. As PKA-null and Gαs mutant embryos also exhibit increased Shh signaling in the neural tube, Gpr161 is a strong candidate for a GPCR that regulates ciliary cAMP levels, and activates PKA in close proximity to the cilia.
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Saikat
authors.initials: S
authors.lastname: Mukhopadhyay
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D002923:Cilia / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005407:Flagella / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D054259:Neural Tube / Q000502:physiology*; D038081:Organogenesis; D011506:Proteins / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction; D000074290:Zinc Finger Protein Gli3
chemical_list: C533095:GPR161 protein, mouse; C465571:Gli3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; C485499:Tulp3 protein, mouse; D000074290:Zinc Finger Protein Gli3; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: G-protein-coupled receptor; hedgehog; neural tube; primary cilium; protein kinase A