title: The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling.
abstract: The primary cilium is required for Sonic hedgehog (Shh) signaling in vertebrates. In contrast to mutants affecting ciliary assembly, mutations in the intraflagellar transport complex A (IFT-A) paradoxically cause increased Shh signaling. We previously showed that the IFT-A complex, in addition to its canonical role in retrograde IFT, binds to the tubby-like protein, Tulp3, and recruits it to cilia. Here, we describe a conserved vertebrate G-protein-coupled receptor, Gpr161, which localizes to primary cilia in a Tulp3/IFT-A-dependent manner. Complete loss of Gpr161 in mouse causes midgestation lethality and increased Shh signaling in the neural tube, phenocopying Tulp3/IFT-A mutants. Constitutive Gpr161 activity increases cAMP levels and represses Shh signaling by determining the processing of Gli3 to its repressor form. Conversely, Shh signaling directs Gpr161 to be internalized from cilia, preventing its activity. Thus, Gpr161 defines a morphogenetic pathway coupling protein kinase A activation to Shh signaling during neural tube development.
authors: Department of Research Oncology, Genentech Inc., South San Francisco, CA 94080, USA. saikat.mukhopadhyay@utsouthwestern.edu
authors: Saikat
authors: S
authors: Mukhopadhyay
authors: Xiaohui
authors: X
authors: Wen
authors: Navneet
authors: N
authors: Ratti
authors: Alexander
authors: A
authors: Loktev
authors: Linda
authors: L
authors: Rangell
authors: Suzie J
authors: SJ
authors: Scales
authors: Peter K
authors: PK
authors: Jackson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002923:Cilia / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D054259:Neural Tube / Q000378:metabolism*; D010802:Phylogeny; D011506:Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: C533095:GPR161 protein, mouse; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; C465570:Shh protein, mouse; C485499:Tulp3 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases