REVIEW

Hedgehog signaling: mechanisms and evolution

  • Xuan YE ,
  • Aimin LIU
Expand
  • Department of Biology, Eberly College of Science, The Pennsylvania State University, University Park, PA 16802, USA

Received date: 17 Feb 2011

Accepted date: 11 Mar 2011

Published date: 01 Dec 2011

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

Abstract

The Hedgehog (Hh) family of secreted proteins plays essential roles in the development of a wide variety of animal species and underlies multiple human birth defects and cancers. To ensure the proper range of signaling, the Hh proteins are modified with lipids, assembled into water-soluble multimers, and interact with multiple cell surface proteins. In the target cells, a largely conserved intracellular signal transduction pathway, from the cell surface receptor Patched to the Glioma-associated oncogene homolog (Gli) family of transcription factors, mediates the transcriptional responses from fruit flies to mammals. A significant divergence between vertebrates and insects is the vertebrate-specific requirement of cilia for Hh signal transduction and Gli protein activation. Finally, transcription-independent cellular responses to Hh have been described in certain developmental processes. With clinical trial underway to treat Hh-related diseases, more work is urgently needed to reach a more comprehensive understanding of the molecular mechanisms underlying the regulation of Hh signaling in development and diseases.

Cite this article

Xuan YE , Aimin LIU . Hedgehog signaling: mechanisms and evolution[J]. Frontiers in Biology, 2011 , 6(6) : 504 -521 . DOI: 10.1007/s11515-011-1146-2

Acknowledgment

We thank Westley Heydeck, Huiqing Zeng and Jinling Liu for critically reading the manuscript. We apologize to colleagues whose work we failed to include in this short review because of the huge amount of information published in this field. Research activities in our laboratory are supported by grants from NSF, American Heart Association, PKD foundation and a new laboratory start-up fund from the Pennsylvania State University.
1
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

DOI PMID

2
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

DOI PMID

3
Amanai K, Jiang J (2001). Distinct roles of central missing and dispatched in sending the Hedgehog signal. Development, 128(24): 5119–5127

PMID

4
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

DOI PMID

5
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

DOI PMID

6
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

DOI PMID

7
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

PMID

8
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

DOI PMID

9
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

DOI PMID

10
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

DOI PMID

11
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

DOI PMID

12
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

DOI PMID

13
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

PMID

14
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

DOI PMID

15
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

PMID

16
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

DOI PMID

17
Cameron D A, Pennimpede T, Petkovich M (2009). Tulp3 is a critical repressor of mouse hedgehog signaling. Dev Dyn, 238(5): 1140–1149

DOI PMID

18
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

DOI PMID

19
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

DOI PMID

20
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

DOI PMID

21
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

DOI PMID

22
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

DOI PMID

23
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

DOI PMID

24
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

DOI PMID

25
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

DOI PMID

26
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

DOI PMID

27
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

DOI PMID

28
Chen M H, Wilson C W, 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

DOI PMID

29
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

DOI PMID

30
Chen Y, Struhl G (1996). Dual roles for patched in sequestering and transducing Hedgehog. Cell, 87(3): 553–563

DOI PMID

31
Cheng S Y, Bishop J M (2002). Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc Natl Acad Sci USA, 99(8): 5442–5447

DOI PMID

32
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

DOI PMID

33
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

DOI PMID

34
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

DOI PMID

35
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

DOI PMID

36
Chuang P T, McMahon A P (1999). Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature, 397(6720): 617–621

DOI PMID

37
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

DOI PMID

38
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

DOI PMID

39
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

DOI PMID

40
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

DOI PMID

41
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

DOI PMID

42
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

DOI PMID

43
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

DOI PMID

44
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

PMID

45
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

PMID

46
Endoh-Yamagami S, Evangelista M, Wilson D, Wen X, Theunissen J W, 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

DOI PMID

47
Frank-Kamenetsky M, Zhang X M, 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

DOI PMID

48
Gerdes J M, Davis E E, Katsanis N (2009). The vertebrate primary cilium in development, homeostasis, and disease. Cell, 137(1): 32–45

DOI PMID

49
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

DOI PMID

50
Han C, Belenkaya T Y, Wang B, Lin X (2004). Drosophila glypicans control the cell-to-cell movement of Hedgehog by a dynamin-independent process. Development, 131(3): 601–611

DOI PMID

51
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

DOI PMID

52
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

DOI PMID

53
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

DOI PMID

54
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

DOI PMID

55
Hirokawa N, Tanaka Y, Okada Y, Takeda S (2006). Nodal flow and the generation of left-right asymmetry. Cell, 125(1): 33–45

DOI PMID

56
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

DOI PMID

57
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

DOI PMID

58
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 D W (2006). Hippi is essential for node cilia assembly and Sonic hedgehog signaling. Dev Biol, 300(2): 523–533

DOI PMID

59
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

DOI PMID

60
Huangfu D, Anderson K V (2005). Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci USA, 102(32): 11325–11330

DOI PMID

61
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

DOI PMID

62
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

63
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

DOI PMID

64
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

DOI PMID

65
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

DOI PMID

66
Jia J, Tong C, Jiang J (2003). Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its C-terminal tail. Genes Dev, 17(21): 2709–2720

DOI PMID

67
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

DOI PMID

68
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

DOI PMID

69
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

DOI PMID

70
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

DOI PMID

71
Khaliullina H, Panáková D, Eugster C, Riedel F, Carvalho M, Eaton S (2009). Patched regulates Smoothened trafficking using lipoprotein-derived lipids. Development, 136(24): 4111–4121

DOI PMID

72
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

DOI PMID

73
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

DOI PMID

74
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

DOI PMID

75
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

DOI PMID

76
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

DOI PMID

77
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

DOI PMID

78
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

DOI PMID

79
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

DOI PMID

80
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

DOI PMID

81
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

DOI PMID

82
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

PMID

83
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

DOI PMID

84
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

DOI PMID

85
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

DOI PMID

86
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

DOI PMID

87
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

DOI PMID

88
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

DOI PMID

89
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

DOI PMID

90
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

DOI PMID

91
Martinelli D C, Fan C M (2007). Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev, 21(10): 1231–1243

DOI PMID

92
Matise M P, 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

PMID

93
Matise M P, Joyner A L (1999). Gli genes in development and cancer. Oncogene, 18(55): 7852–7859

DOI PMID

94
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

DOI PMID

95
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

DOI PMID

96
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

DOI PMID

97
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

DOI PMID

98
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

PMID

99
Methot N, Basler K (2001). An absolute requirement for Cubitus interruptus in Hedgehog signaling. Development, 128(5): 733–742

PMID

100
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

PMID

101
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

DOI PMID

102
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 protein-coupled receptors into primary cilia. Genes Dev, 24(19): 2180–2193

DOI PMID

103
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

DOI PMID

104
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

DOI PMID

105
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

DOI PMID

106
Nusslein-Volhard C, Wieschaus E (1980). Mutations affecting segment number and polarity in Drosophila. Nature, 287(5785): 795–801

DOI PMID

107
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

DOI PMID

108
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

DOI PMID

109
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

DOI PMID

110
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

DOI PMID

111
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

DOI PMID

112
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

DOI PMID

113
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

DOI PMID

114
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

DOI PMID

115
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

DOI PMID

116
Park H L, Bai C, Platt K A, Matise M P, 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

117
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

DOI PMID

118
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

DOI PMID

119
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

DOI PMID

120
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 acid-modified form of human Sonic hedgehog. J Biol Chem, 273(22): 14037–14045

DOI PMID

121
Porter J A, Ekker S C, Park W J, 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

DOI PMID

122
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

DOI PMID

123
Porter J A, Young K E, Beachy P A (1996b). Cholesterol modification of hedgehog signaling proteins in animal development. Science, 274(5285): 255–259

DOI PMID

124
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

PMID

125
Price M A, Kalderon D (1999). Proteolysis of cubitus interruptus in Drosophila requires phosphorylation by protein kinase A. Development, 126(19): 4331–4339

PMID

126
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

DOI PMID

127
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

DOI PMID

128
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

DOI PMID

129
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

DOI PMID

130
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

DOI PMID

131
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

DOI PMID

132
Rohatgi R, Milenkovic L, Scott M P (2007). Patched1 regulates hedgehog signaling at the primary cilium. Science, 317(5836): 372–376

DOI PMID

133
Rohatgi R, Snell W J (2010). The ciliary membrane. Curr Opin Cell Biol, 22(4): 541–546

DOI PMID

134
Rosenbaum J L, Witman G B (2002). Intraflagellar transport. Nat Rev Mol Cell Biol, 3(11): 813–825

DOI PMID

135
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

DOI PMID

136
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

DOI PMID

137
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

DOI PMID

138
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

DOI PMID

139
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

DOI PMID

140
Stone D M, Hynes M, Armanini M, Swanson T A, Gu Q, Johnson R L, Scott M P, 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

DOI PMID

141
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

PMID

142
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

DOI PMID

143
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

DOI PMID

144
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

DOI PMID

145
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

DOI PMID

146
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

DOI PMID

147
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

DOI PMID

148
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

DOI PMID

149
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

DOI PMID

150
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

DOI PMID

151
Varjosalo M, Li S P, Taipale J (2006). Divergence of hedgehog signal transduction mechanism between Drosophila and mammals. Dev Cell, 10(2): 177–186

DOI PMID

152
Von Hoff D D, LoRusso P M, Rudin C M, Reddy J C, Yauch R L, Tibes R, Weiss G J, Borad M J, Hann C L, Brahmer J R, Mackey H M, Lum B L, Darbonne W C, 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

DOI PMID

153
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

DOI PMID

154
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

DOI PMID

155
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

DOI PMID

156
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

DOI PMID

157
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

DOI PMID

158
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

DOI PMID

159
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

DOI PMID

160
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

DOI PMID

161
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

DOI PMID

162
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

DOI PMID

163
Yan D, Wu Y, Yang Y, Belenkaya T Y, Tang X, Lin X (2010). The cell-surface proteins Dally-like and Ihog differentially regulate Hedgehog signaling strength and range during development. Development, 137(12): 2033–2044

DOI PMID

164
Yao S, Lum L, Beachy P (2006). The ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell, 125(2): 343–357

DOI PMID

165
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

DOI PMID

166
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

DOI PMID

167
Yin Y, Bangs F, Paton I R, Prescott A, James J, Davey M G, Whitley P, Genikhovich G, Technau U, Burt D W, Tickle C (2009). The Talpid3 gene (KIAA0586) encodes a centrosomal protein that is essential for primary cilia formation. Development, 136(4): 655–664

DOI PMID

168
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

DOI PMID

169
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

DOI PMID

170
Zeng X, Goetz J A, Suber L M, Scott W J Jr, Schreiner C M, Robbins D J (2001). A freely diffusible form of Sonic hedgehog mediates long-range signalling. Nature, 411(6838): 716–720

DOI PMID

171
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

DOI PMID

172
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

DOI PMID

173
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

DOI PMID

174
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

DOI PMID

175
Zhao Y, Tong C, Jiang J (2007). Hedgehog regulates smoothened activity by inducing a conformational switch. Nature, 450(7167): 252–258

DOI PMID

176
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

DOI PMID

177
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

DOI PMID

Outlines

/