Hedgehog signaling: mechanisms and evolution

Alcedo J, Ayzenzon M, Von Ohlen T, Noll M, Hooper J E (1996). The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal. Cell, 86(2): 221–232 Allen B L, Tenzen T, McMahon A P (2007). The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Genes Dev, 21(10): 1244–1257 Amanai K, Jiang J (2001). Distinct roles of central missing and dispatched in sending the Hedgehog signal. Development, 128(24): 5119–5127 Apionishev S, Katanayeva N M, Marks S A, Kalderon D, Tomlinson A (2005). Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction. Nat Cell Biol, 7(1): 86–92 Asaoka Y, Kanai F, Ichimura T, Tateishi K, Tanaka Y, Ohta M, Seto M, Tada M, Ijichi H, Ikenoue T, Kawabe T, Isobe T, Yaffe M B, Omata M (2010). Identification of a suppressive mechanism for Hedgehog signaling through a novel interaction of Gli with 14-3-3. J Biol Chem, 285(6): 4185–4194 Aza-Blanc P, Ramírez-Weber F A, Laget M P, Schwartz C, Kornberg T B (1997). Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell, 89(7): 1043–1053 Bai C B, Auerbach W, Lee J S, Stephen D, Joyner A L (2002). Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development, 129(20): 4753–4761 Bai C B, Stephen D, Joyner A L (2004). All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev Cell, 6(1): 103–115 Barzi M, Berenguer J, Menendez A, Alvarez-Rodriguez R, Pons S (2010). Sonic-hedgehog-mediated proliferation requires the localization of PKA to the cilium base. J Cell Sci, 123(Pt 1): 62–69 Bellaiche Y, The I, Perrimon N (1998). Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature, 394(6688): 85–88 Bergeron S A, Tyurina O V, Miller E, Bagas A, Karlstrom R O (2011). Brother of cdo (umleitung) is cell-autonomously required for Hedgehog-mediated ventral CNS patterning in the zebrafish. Development, 138(1): 75–85 Bitgood M J, Shen L, McMahon A P (1996). Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr Biol, 6(3): 298–304 Bumcrot D A, Takada R, McMahon A P (1995). Proteolytic processing yields two secreted forms of sonic hedgehog. Mol Cell Biol, 15(4): 2294–2303 Burke R, Nellen D, Bellotto M, Hafen E, Senti K A, Dickson B J, Basler K (1999). Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell, 99(7): 803–815 Byrd N, Becker S, Maye P, Narasimhaiah R, St-Jacques B, Zhang X, McMahon J, McMahon A, Grabel L (2002). Hedgehog is required for murine yolk sac angiogenesis. Development, 129(2): 361–372 Callejo A, Torroja C, Quijada L, Guerrero I (2006). Hedgehog lipid modifications are required for Hedgehog stabilization in the extracellular matrix. Development, 133(3): 471–483 Cameron D A, Pennimpede T, Petkovich M (2009). Tulp3 is a critical repressor of mouse hedgehog signaling. Dev Dyn, 238(5): 1140–1149 Canettieri G, Di Marcotullio L, Greco A, Coni S, Antonucci L, Infante P, Pietrosanti L, De Smaele E, Ferretti E, Miele E, Pelloni M, De Simone G, Pedone E M, Gallinari P, Giorgi A, Steinkühler C, Vitagliano L, Pedone C, Schinin M E, Screpanti I, Gulino A (2010). Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation. Nat Cell Biol, 12(2): 132–142 Capurro M I, Xu P, Shi W, Li F, Jia A, Filmus J (2008). Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding. Dev Cell, 14(5): 700–711 Caspary T, García-García M J, Huangfu D, Eggenschwiler J T, Wyler M R, Rakeman A S, Alcorn H L, Anderson K V (2002). Mouse Dispatched homolog1 is required for long-range, but not juxtacrine, Hh signaling. Curr Biol, 12(18): 1628–1632 Caspary T, Larkins C E, Anderson K V (2007). The graded response to Sonic Hedgehog depends on cilia architecture. Dev Cell, 12(5): 767–778 Chamoun Z, Mann R K, Nellen D, von Kessler D P, Bellotto M, Beachy P A, Basler K (2001). Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science, 293(5537): 2080–2084 Charron F, Stein E, Jeong J, McMahon A P, Tessier-Lavigne M (2003). The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance. Cell, 113(1): 11–23 Chen J K, Taipale J, Cooper M K, Beachy P A (2002a). Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev, 16(21): 2743–2748 Chen J K, Taipale J, Young K E, Maiti T, Beachy P A (2002b). Small molecule modulation of Smoothened activity. Proc Natl Acad Sci USA, 99(22): 14071–14076 Chen M H, Gao N, Kawakami T, Chuang P T (2005). Mice deficient in the fused homolog do not exhibit phenotypes indicative of perturbed hedgehog signaling during embryonic development. Mol Cell Biol, 25(16): 7042–7053 Chen M H, Li Y J, Kawakami T, Xu S M, Chuang P T (2004). Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes Dev, 18(6): 641–659 Chen MH, Wilson CW, Li Y J, Law K K, Lu C S, Gacayan R, Zhang X, Hui C C, Chuang P T (2009). Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes Dev, 23(16): 1910–1928 Chen Y, Gallaher N, Goodman R H, Smolik S M (1998). Protein kinase A directly regulates the activity and proteolysis of cubitus interruptus. Proc Natl Acad Sci USA, 95(5): 2349–2354 Chen Y, Struhl G (1996). Dual roles for patched in sequestering and transducing Hedgehog. Cell, 87(3): 553–563 Cheng S Y, Bishop J M (2002). Suppressor of Fused represses Glimediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc Natl Acad Sci USA, 99(8): 5442–5447 Cheung H O, Zhang X, Ribeiro A, Mo R, Makino S, Puviindran V, Law K K, Briscoe J, Hui C C (2009). The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling. Sci Signal, 2(76): ra29 Chiang C, Litingtung Y, Harris M P, Simandl B K, Li Y, Beachy P A, Fallon J F (2001). Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. Dev Biol, 236(2): 421–435 Chiang C, Litingtung Y, Lee E, Young K E, Corden J L, Westphal H, Beachy P A (1996). Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature, 383(6599): 407–413 Chuang P T, Kawcak T, McMahon A P (2003). Feedback control of mammalian Hedgehog signaling by the Hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung. Genes Dev, 17(3): 342–347 Chuang P T, McMahon A P (1999). Vertebrate Hedgehog signaling modulated by induction of a Hedgehog-binding protein. Nature, 397(6720): 617–621 Cooper A F, Yu K P, Brueckner M, Brailey L L, Johnson L, McGrath J M, Bale A E (2005). Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Development, 132(19): 4407–4417 Corbit K C, Aanstad P, Singla V, Norman A R, Stainier D Y, Reiter J F (2005). Vertebrate Smoothened functions at the primary cilium. Nature, 437(7061): 1018–1021 Cox B, Briscoe J, Ulloa F (2010). SUMOylation by Pias1 regulates the activity of the Hedgehog dependent Gli transcription factors. PLoS ONE, 5(8): e11996 Dawber R J, Hebbes S, Herpers B, Docquier F, van den Heuvel M (2005). Differential range and activity of various forms of the Hedgehog protein. BMC Dev Biol, 5(1): 21 Denef N, Neubüser D, Perez L, Cohen S M (2000). Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell, 102(4): 521–531 Desbordes S C, Sanson B (2003). The glypican Dally-like is required for Hedgehog signalling in the embryonic epidermis of Drosophila. Development, 130(25): 6245–6255 Ding Q, Fukami S, Meng X, Nishizaki Y, Zhang X, Sasaki H, Dlugosz A, Nakafuku M, Hui C (1999). Mouse suppressor of fused is a negative regulator of sonic hedgehog signaling and alters the subcellular distribution of Gli1. Curr Biol, 9(19): 1119–1122 Ding Q, Motoyama J, Gasca S, Mo R, Sasaki H, Rossant J, Hui C C (1998). Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Development, 125(14): 2533–2543 Dyer M A, Farrington S M, Mohn D, Munday J R, Baron M H (2001). Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development, 128(10): 1717–1730 Endoh-Yamagami S, Evangelista M, Wilson D, Wen X, Theunissen JW, Phamluong K, Davis M, Scales S J, Solloway M J, de Sauvage F J, Peterson A S (2009). The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr Biol, 19(15): 1320–1326 Frank-Kamenetsky M, Zhang XM, Bottega S, Guicherit O, Wichterle H, Dudek H, Bumcrot D, Wang F Y, Jones S, Shulok J, Rubin L L, Porter J A (2002). Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J Biol, 1(2): 10 Gerdes J M, Davis E E, Katsanis N (2009). The vertebrate primary cilium in development, homeostasis, and disease. Cell, 137(1): 32–45 Goodrich L V, Milenković L, Higgins K M, Scott M P (1997). Altered neural cell fates and medulloblastoma in mouse patched mutants. Science, 277(5329): 1109–1113 Han C, Belenkaya T Y, Wang B, Lin X (2004). Drosophila glypicans control the cell-to-cell movement of Hedgehog by a dynaminindependent process. Development, 131(3): 601–611 Han Y G, Kwok B H, Kernan M J (2003). Intraflagellar transport is required in Drosophila to differentiate sensory cilia but not sperm. Curr Biol, 13(19): 1679–1686 Haycraft C J, Banizs B, Aydin-Son Y, Zhang Q, Michaud E J, Yoder B K (2005). Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet, 1(4): e53 Heberlein U, Wolff T, Rubin G M (1993). The TGF beta homolog dpp and the segment polarity gene hedgehog are required for propagation of a morphogenetic wave in the Drosophila retina. Cell, 75(5): 913–926 Heydeck W, Zeng H, Liu A (2009). Planar cell polarity effector gene Fuzzy regulates cilia formation and Hedgehog signal transduction in mouse. Dev Dyn, 238(12): 3035–3042 Hirokawa N, Tanaka Y, Okada Y, Takeda S (2006). Nodal flow and the generation of left-right asymmetry. Cell, 125(1): 33–45 Hooper J E, Scott M P (1989). The Drosophila patched gene encodes a putative membrane protein required for segmental patterning. Cell, 59(4): 751–765 Hoover A N, Wynkoop A, Zeng H, Jia J, Niswander L A, Liu A (2008). C2cd3 is required for cilia formation and Hedgehog signaling in mouse. Development, 135(24): 4049–4058 Houde C, Dickinson R J, Houtzager V M, Cullum R, Montpetit R, Metzler M, Simpson E M, Roy S, Hayden M R, Hoodless P A, Nicholson DW (2006). Hippi is essential for node cilia assembly and Sonic hedgehog signaling. Dev Biol, 300(2): 523–533 Hu Q, Milenkovic L, Jin H, Scott M P, Nachury M V, Spiliotis E T, Nelson W J (2010). A septin diffusion barrier at the base of the primary cilium maintains ciliary membrane protein distribution. Science, 329(5990): 436–439 Huangfu D, Anderson K V (2005). Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci USA, 102(32): 11325–11330 Huangfu D, Liu A, Rakeman A S, Murcia N S, Niswander L, Anderson K V (2003). Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature, 426(6962): 83–87 Hui C C, Joyner A L (1993). A mouse model of greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Nat Genet, 3: 241–246 Humke E W, Dorn K V, Milenkovic L, Scott M P, Rohatgi R (2010). The output of Hedgehog signaling is controlled by the dynamic association between suppressor of Fused and the Gli proteins. Genes Dev, 24(7): 670–682 Jia H, Liu Y, Yan W, Jia J (2009a). PP4 and PP2A regulate Hedgehog signaling by controlling Smo and Ci phosphorylation. Development, 136(2): 307–316 Jia J, Kolterud A, Zeng H, Hoover A, Teglund S, Toftgård R, Liu A (2009b). Suppressor of Fused inhibits mammalian Hedgehog signaling in the absence of cilia. Dev Biol, 330(2): 452–460 Jia J, Tong C, Jiang J (2003). Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its Cterminal tail. Genes Dev, 17(21): 2709–2720 Jia J, Tong C, Wang B, Luo L, Jiang J (2004). Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature, 432(7020): 1045–1050 Jiang J, Struhl G (1998). Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature, 391(6666): 493–496 Jin H, White S R, Shida T, Schulz S, Aguiar M, Gygi S P, Bazan J F, Nachury M V (2010). The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell, 141(7): 1208–1219 Kawakami T, Kawcak T, Li Y J, Zhang W, Hu Y, Chuang P T (2002). Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development, 129(24): 5753–5765 Khaliullina H, Panáková D, Eugster C, Riedel F, Carvalho M, Eaton S (2009). Patched regulates Smoothened trafficking using lipoproteinderived lipids. Development, 136(24): 4111–4121 Kovacs J J, Whalen E J, Liu R, Xiao K, Kim J, Chen M, Wang J, Chen W, Lefkowitz R J (2008). Beta-arrestin-mediated localization of smoothened to the primary cilium. Science, 320(5884): 1777–1781 Koziel L, Kunath M, Kelly O G, Vortkamp A (2004). Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell, 6(6): 801–813 Kraus P, Fraidenraich D, Loomis C A (2001). Some distal limb structures develop in mice lacking Sonic hedgehog signaling. Mech Dev, 100(1): 45–58 Krauss S, Concordet J P, Ingham P W (1993). A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell, 75(7): 1431–1444 Lee J D, Treisman J E (2001). Sightless has homology to transmembrane acyltransferases and is required to generate active Hedgehog protein. Curr Biol, 11(14): 1147–1152 Lee J J, Ekker S C, von Kessler D P, Porter J A, Sun B I, Beachy P A (1994). Autoproteolysis in hedgehog protein biogenesis. Science, 266(5190): 1528–1537 Lee Y, Miller H L, Russell H R, Boyd K, Curran T, McKinnon P J (2006). Patched2 modulates tumorigenesis in patched1 heterozygous mice. Cancer Res, 66(14): 6964–6971 Lei Q, Zelman A K, Kuang E, Li S, Matise M P (2004). Transduction of graded Hedgehog signaling by a combination of Gli2 and Gli3 activator functions in the developing spinal cord. Development, 131(15): 3593–3604 Lewis P M, Dunn M P, McMahon J A, Logan M, Martin J F, St-Jacques B, McMahon A P (2001). Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell, 105(5): 599–612 Li Y, Zhang H, Litingtung Y, Chiang C (2006). Cholesterol modification restricts the spread of Shh gradient in the limb bud. Proc Natl Acad Sci USA, 103(17): 6548–6553 Liem K F Jr, He M, Ocbina P J, Anderson K V (2009). Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling. Proc Natl Acad Sci U S A, 106(32): 13377–13382 Litingtung Y, Chiang C (2000). Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3. Nat Neurosci, 3(10): 979–985 Litingtung Y, Dahn R D, Li Y, Fallon J F, Chiang C (2002). Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature, 418(6901): 979–983 Liu A, Wang B, Niswander L A (2005). Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development, 132(13): 3103–3111 Lum L, Yao S, Mozer B, Rovescalli A, Von Kessler D, Nirenberg M, Beachy P A (2003a). Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells. Science, 299(5615): 2039–2045 Lum L, Zhang C, Oh S, Mann R K, von Kessler D P, Taipale J, Weis-Garcia F, Gong R, Wang B, Beachy P A (2003b). Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2. Mol Cell, 12(5): 1261–1274 Ma C, Zhou Y, Beachy P A, Moses K (1993). The segment polarity gene hedgehog is required for progression of the morphogenetic furrow in the developing Drosophila eye. Cell, 75(5): 927–938 Ma Y, Erkner A, Gong R, Yao S, Taipale J, Basler K, Beachy P A (2002). Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell, 111(1): 63–75 Marigo V, Davey R A, Zuo Y, Cunningham J M, Tabin C J (1996). Biochemical evidence that patched is the Hedgehog receptor. Nature, 384(6605): 176–179 Martinelli D C, Fan C M (2007). Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev, 21(10): 1231–1243 Matise MP, Epstein D J, Park H L, Platt K A, Joyner A L (1998). Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system. Development, 125: 2759–2770 Matise M P, Joyner A L (1999). Gli genes in development and cancer. Oncogene, 18(55): 7852–7859 May S R, Ashique A M, Karlen M, Wang B, Shen Y, Zarbalis K, Reiter J, Ericson J, Peterson A S (2005). Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev Biol, 287(2): 378–389 McCarthy R A, Barth J L, Chintalapudi M R, Knaak C, Argraves W S (2002). Megalin functions as an endocytic sonic hedgehog receptor. J Biol Chem, 277(28): 25660–25667 McLellan J S, Zheng X, Hauk G, Ghirlando R, Beachy P A, Leahy D J (2008). The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla. Nature, 455(7215): 979–983 Merchant M, Evangelista M, Luoh S M, Frantz G D, Chalasani S, Carano R A, van Hoy M, Ramirez J, Ogasawara A K, McFarland L M, Filvaroff E H, French D M, de Sauvage F J (2005). Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. Mol Cell Biol, 25(16): 7054–7068 Methot N, Basler K (2000). Suppressor of fused opposes hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus. Development, 127(18): 4001–4010 Methot N, Basler K (2001). An absolute requirement for Cubitus interruptus in Hedgehog signaling. Development, 128(5): 733–742 Micchelli C A, The I, Selva E, Mogila V, Perrimon N (2002). Rasp, a putative transmembrane acyltransferase, is required for Hedgehog signaling. Development, 129(4): 843–851 Milenkovic L, Scott M P, Rohatgi R (2009). Lateral transport of Smoothened from the plasma membrane to the membrane of the cilium. J Cell Biol, 187(3): 365–374 Mukhopadhyay S, Wen X, Chih B, Nelson C D, Lane W S, Scales S J, Jackson P K (2010). TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G proteincoupled receptors into primary cilia. Genes Dev, 24(19): 2180–2193 Nachury M V, Loktev A V, Zhang Q, Westlake C J, Peränen J, Merdes A, Slusarski D C, Scheller R H, Bazan J F, Sheffield V C, Jackson P K (2007). A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell, 129(6): 1201–1213 Nakano Y, Guerrero I, Hidalgo A, Taylor A, Whittle J R, Ingham P W (1989). A protein with several possible membrane-spanning domains encoded by the Drosophila segment polarity gene patched. Nature, 341(6242): 508–513 Norman R X, Ko H W, Huang V, Eun C M, Abler L L, Zhang Z, Sun X, Eggenschwiler J T (2009). Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling. Hum Mol Genet, 18(10): 1740–1754 Nusslein-Volhard C, Wieschaus E (1980). Mutations affecting segment number and polarity in Drosophila. Nature, 287(5785): 795–801 Nybakken K, Vokes S A, Lin T Y, McMahon A P, Perrimon N (2005). A genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signaling pathway. Nat Genet, 37(12): 1323–1332 Ocbina P J, Anderson K V (2008). Intraflagellar transport, cilia, and mammalian Hedgehog signaling: analysis in mouse embryonic fibroblasts. Dev Dyn, 237(8): 2030–2038 Ogden S K, Ascano M Jr, Stegman M A, Suber L M, Hooper J E, Robbins D J (2003). Identification of a functional interaction between the transmembrane protein Smoothened and the kinesin-related protein Costal2. Curr Biol, 13(22): 1998–2003 Ogden S K, Fei D L, Schilling N S, Ahmed Y F, Hwa J, Robbins D J (2008). G protein Galphai functions immediately downstream of Smoothened in Hedgehog signalling. Nature, 456(7224): 967–970 Okada A, Charron F, Morin S, Shin D S, Wong K, Fabre P J, Tessier-Lavigne M, McConnell S K (2006). Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature, 444(7117): 369–373 Orenic T V, Slusarski D C, Kroll K L, Holmgren R A (1990). Cloning and characterization of the segment polarity gene cubitus interruptus Dominant of Drosophila. Genes Dev, 4(6): 1053–1067 Paces-Fessy M, Boucher D, Petit E, Paute-Briand S, Blanchet-Tournier M F (2004). The negative regulator of Gli, suppressor of fused (Sufu), interacts with SAP18, Galectin3 and other nuclear proteins. Biochem J, 378(Pt 2): 353–362 Pan Y, Bai C B, Joyner A L, Wang B (2006). Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol, 26(9): 3365–3377 Panakova D, Sprong H, Marois E, Thiele C, Eaton S (2005). Lipoprotein particles are required for Hedgehog and Wingless signalling. Nature, 435(7038): 58–65 Park H L, Bai C, Platt K A, Matise MP, Beeghly A, Hui C C, Nakashima M, Joyner A L (2000). Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development, 127: 1593–1605 Park T J, Haigo S L, Wallingford J B (2006). Ciliogenesis defects in embryos lacking inturned or fuzzy function are associated with failure of planar cell polarity and Hedgehog signaling. Nat Genet, 38(3): 303–311 Patterson V L, Damrau C, Paudyal A, Reeve B, Grimes D T, Stewart M E, Williams D J, Siggers P, Greenfield A, Murdoch J N (2009). Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway. Hum Mol Genet, 18(10): 1719–1739 Pearse R V 2nd, Collier L S, Scott M P, Tabin C J (1999). Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators. Dev Biol, 212(2): 323–336 Pepinsky R B, Zeng C, Wen D, Rayhorn P, Baker D P, Williams K P, Bixler S A, Ambrose C M, Garber E A, Miatkowski K, Taylor F R, Wang E A, Galdes A (1998). Identification of a palmitic acidmodified form of human Sonic hedgehog. J Biol Chem, 273(22): 14037–14045 Porter J A, Ekker S C, Park WJ, von Kessler D P, Young K E, Chen C H, Ma Y, Woods A S, Cotter R J, Koonin E V, Beachy P A (1996a). Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. Cell, 86(1): 21–34 Porter J A, von Kessler D P, Ekker S C, Young K E, Lee J J, Moses K, Beachy P A (1995). The product of hedgehog autoproteolytic cleavage active in local and long-range signalling. Nature, 374(6520): 363–366 Porter J A, Young K E, Beachy P A (1996b). Cholesterol modification of hedgehog signaling proteins in animal development. Science, 274(5285): 255–259 Preat T (1992). Characterization of Suppressor of fused, a complete suppressor of the fused segment polarity gene of Drosophila melanogaster. Genetics, 132(3): 725–736 Price M A, Kalderon D (1999). Proteolysis of cubitus interruptus in Drosophila requires phosphorylation by protein kinase A. Development, 126(19): 4331–4339 Price M A, Kalderon D (2002). Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1. Cell, 108(6): 823–835 Qin J, Lin Y, Norman R X, Ko H W, Eggenschwiler J T (2011). Intraflagellar transport protein 122 antagonizes Sonic Hedgehog signaling and controls ciliary localization of pathway components. Proc Natl Acad Sci USA, 108(4): 1456–1461 Rink J C, Gurley K A, Elliott S A, Sánchez Alvarado A (2009). Planarian Hh signaling regulates regeneration polarity and links Hh pathway evolution to cilia. Science, 326(5958): 1406–1410 Robbins D J, Nybakken K E, Kobayashi R, Sisson J C, Bishop J M, Thérond P P (1997). Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein costal2. Cell, 90(2): 225–234 Roelink H, Porter J A, Chiang C, Tanabe Y, Chang D T, Beachy P A, Jessell T M (1995). Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell, 81(3): 445–455 Rohatgi R, Milenkovic L, Corcoran R B, Scott M P (2009). Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc Natl Acad Sci USA, 106(9): 3196–3201 Rohatgi R, Milenkovic L, Scott M P (2007). Patched1 regulates hedgehog signaling at the primary cilium. Science, 317(5836): 372–376 Rohatgi R, Snell WJ (2010). The ciliary membrane. Curr Opin Cell Biol, 22(4): 541–546 Rosenbaum J L, Witman G B (2002). Intraflagellar transport. Nat Rev Mol Cell Biol, 3(11): 813–825 Ruel L, Rodriguez R, Gallet A, Lavenant-Staccini L, Thérond P P (2003). Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog. Nat Cell Biol, 5(10): 907–913 Sarpal R, Todi S V, Sivan-Loukianova E, Shirolikar S, Subramanian N, Raff E C, Erickson J W, Ray K, Eberl D F (2003). Drosophila KAP interacts with the kinesin II motor subunit KLP64D to assemble chordotonal sensory cilia, but not sperm tails. Curr Biol, 13(19): 1687–1696 Sisson B E, Ziegenhorn S L, Holmgren R A (2006). Regulation of Ci and Su(fu) nuclear import in Drosophila. Dev Biol, 294(1): 258–270 Sisson J C, Ho K S, Suyama K, Scott M P (1997). Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway. Cell, 90(2): 235–245 St-Jacques B, Hammerschmidt M, McMahon A P (1999). Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev, 13(16): 2072–2086 Stone D M, Hynes M, Armanini M, Swanson T A, Gu Q, Johnson R L, Scott MP, Pennica D, Goddard A, Phillips H, Noll M, Hooper J E, de Sauvage F, Rosenthal A (1996). The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature, 384(6605): 129–134 Stone D M, Murone M, Luoh S, Ye W, Armanini M P, Gurney A, Phillips H, Brush J, Goddard A, de Sauvage F J, Rosenthal A (1999). Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli. J Cell Sci, 112(Pt 23): 4437–4448 Svard J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergström A, Ericson J, Toftgård R, Teglund S (2006). Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell, 10(2): 187–197 Tabata T, Kornberg T B (1994). Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell, 76(1): 89–102 Taipale J, Cooper M K, Maiti T, Beachy P A (2002). Patched acts catalytically to suppress the activity of Smoothened. Nature, 418(6900): 892–897 Tay S Y, Ingham P W, Roy S (2005). A homologue of the Drosophila kinesin-like protein Costal2 regulates Hedgehog signal transduction in the vertebrate embryo. Development, 132(4): 625–634 Tenzen T, Allen B L, Cole F, Kang J S, Krauss R S, McMahon A P (2006). The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev Cell, 10(5): 647–656 The I, Bellaiche Y, Perrimon N (1999). Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan. Mol Cell, 4(4): 633–639 Tian H, Jeong J, Harfe B D, Tabin C J, McMahon A P (2005). Mouse Disp1 is required in sonic hedgehog-expressing cells for paracrine activity of the cholesterol-modified ligand. Development, 132(1): 133–142 Tran P V, Haycraft C J, Besschetnova T Y, Turbe-Doan A, Stottmann R W, Herron B J, Chesebro A L, Qiu H, Scherz P J, Shah J V, Yoder B K, Beier D R (2008). THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat Genet, 40(4): 403–410 Tukachinsky H, Lopez L V, Salic A (2010). A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes. J Cell Biol, 191(2): 415–428 Varjosalo M, Li S P, Taipale J (2006). Divergence of hedgehog signal transduction mechanism between Drosophila and mammals. Dev Cell, 10(2): 177–186 Von Hoff D D, LoRusso P M, Rudin C M, Reddy J C, Yauch R L, Tibes R, Weiss G J, Borad MJ, Hann C L, Brahmer J R, Mackey HM, Lum B L, Darbonne WC, Marsters J C Jr, de Sauvage F J, Low J A (2009). Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med, 361(12): 1164–1172 Wang B, Fallon J F, Beachy P A (2000a). Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell, 100(4): 423–434 Wang C, Pan Y, Wang B (2010). Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors. Development, 137(12): 2001–2009 Wang G, Amanai K, Wang B, Jiang J (2000b). Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of cubitus interruptus. Genes Dev, 14(22): 2893–2905 Wang Y, Zhou Z, Walsh C T, McMahon A P (2009). Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation. Proc Natl Acad Sci USA, 106(8): 2623–2628 Wen X, Lai C K, Evangelista M, Hongo J A, de Sauvage F J, Scales S J (2010). Kinetics of hedgehog-dependent full-length Gli3 accumulation in primary cilia and subsequent degradation. Mol Cell Biol, 30(8): 1910–1922 Wijgerde M, McMahon J A, Rule M, McMahon A P (2002). A direct requirement for Hedgehog signaling for normal specification of all ventral progenitor domains in the presumptive mammalian spinal cord. Genes Dev, 16(22): 2849–2864 Williams E H, Pappano W N, Saunders A M, Kim M S, Leahy D J, Beachy P A (2010). Dally-like core protein and its mammalian homologues mediate stimulatory and inhibitory effects on Hedgehog signal response. Proc Natl Acad Sci USA, 107(13): 5869–5874 Wilson C W, Chen M H, Chuang P T (2009a). Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium. PLoS ONE, 4(4): e5182 Wilson C W, Nguyen C T, Chen M H, Yang J H, Gacayan R, Huang J, Chen J N, Chuang P T (2009b). Fused has evolved divergent roles in vertebrate Hedgehog signalling and motile ciliogenesis. Nature, 459(7243): 98–102 Yam P T, Langlois S D, Morin S, Charron F (2009). Sonic hedgehog guides axons through a noncanonical, Src-family-kinase-dependent signaling pathway. Neuron, 62(3): 349–362 Yan D, Wu Y, Yang Y, Belenkaya T Y, Tang X, Lin X (2010). The cellsurface proteins Dally-like and Ihog differentially regulate Hedgehog signaling strength and range during development. Development, 137(12): 2033–2044 Yao S, Lum L, Beachy P (2006). The ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell, 125(2): 343–357 Yauch R L, Dijkgraaf G J, Alicke B, Januario T, Ahn C P, Holcomb T, Pujara K, Stinson J, Callahan C A, Tang T, Bazan J F, Kan Z, Seshagiri S, Hann C L, Gould S E, Low J A, Rudin C M, de Sauvage F J (2009). Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science, 326(5952): 572–574 Yavari A, Nagaraj R, Owusu-Ansah E, Folick A, Ngo K, Hillman T, Call G, Rohatgi R, Scott M P, Banerjee U (2010). Role of lipid metabolism in smoothened derepression in hedgehog signaling. Dev Cell, 19(1): 54–65 Yin Y, Bangs F, Paton I R, Prescott A, James J, Davey M G, Whitley P, Genikhovich G, Technau U, Burt DW, Tickle C (2009). The Talpid3 gene (KIAA0586) encodes a centrosomal protein that is essential for primary cilia formation. Development, 136(4): 655–664 Zeng H, Hoover A N, Liu A (2010a). PCP effector gene Inturned is an important regulator of cilia formation and embryonic development in mammals. Dev Biol, 339(2): 418–428 Zeng H, Jia J, Liu A (2010b). Coordinated translocation of mammalian Gli proteins and suppressor of fused to the primary cilium. PLoS ONE, 5(12): e15900 Zeng X, Goetz J A, Suber LM, Scott WJ Jr, Schreiner CM, Robbins D J (2001). A freely diffusible form of Sonic hedgehog mediates longrange signalling. Nature, 411(6838): 716–720 Zhang C, Williams E H, Guo Y, Lum L, Beachy P A (2004). Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Proc Natl Acad Sci USA, 101(52): 17900–17907 Zhang Q, Shi Q, Chen Y, Yue T, Li S, Wang B, Jiang J (2009). Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase. Proc Natl Acad Sci USA, 106(50): 21191–21196 Zhang W, Zhao Y, Tong C, Wang G, Wang B, Jia J, Jiang J (2005). Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Dev Cell, 8(2): 267–278 Zhang X M, Ramalho-Santos M, McMahon A P (2001). Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell, 106(2): 781–792 Zhao Y, Tong C, Jiang J (2007). Hedgehog regulates smoothened activity by inducing a conformational switch. Nature, 450(7167): 252–258 Zheng X, Mann R K, Sever N, Beachy P A (2010). Genetic and biochemical definition of the Hedgehog receptor. Genes Dev, 24(1): 57–71 Zhu A J, Zheng L, Suyama K, Scott M P (2003). Altered localization of Drosophila Smoothened protein activates Hedgehog signal transduction. Genes Dev, 17(10): 1240–1252