title: Intraflagellar transport protein 122 antagonizes Sonic Hedgehog signaling and controls ciliary localization of pathway components.
abstract: Primary cilia are required for proper Sonic Hedgehog (Shh) signaling in mammals. However, their role in the signal transduction process remains unclear. We have identified sister of open brain (sopb), a null allele of mouse Intraflagellar transport protein 122 (Ift122). IFT122 negatively regulates the Shh pathway in the cilium at a step downstream of the Shh ligand and the transmembrane protein Smoothened, but upstream of the Gli2 transcription factor. Ift122(sopb) mutants generate primary cilia, but they show features of defective retrograde intraflagellar transport. IFT122 controls the ciliary localization of Shh pathway regulators in different ways. Disruption of IFT122 leads to accumulation of Gli2 and Gli3 at cilia tips while blocking the ciliary localization of the antagonist TULP3. Suppressor of Fused and Smoothened localize to the cilium through an IFT122-independent mechanism. We propose that the balance between positive and negative regulators of the Shh pathway at the cilium tip controls the output of the pathway and that Shh signaling regulates this balance through intraflagellar transport.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Qin
authors.forename: Yulian
authors.initials: Y
authors.lastname: Lin
authors.forename: Ryan X
authors.initials: RX
authors.lastname: Norman
authors.forename: Hyuk W
authors.initials: HW
authors.lastname: Ko
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Eggenschwiler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002923:Cilia / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D003598:Cytoskeletal Proteins; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C000618551:Gli2 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; C534510:Ift122 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; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; C485499:Tulp3 protein, mouse; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; D049452:Green Fluorescent Proteins