Hedgehog signaling: mechanisms and evolution

doi:10.1007/s11515-011-1146-2

Front Biol

2011, Vol. 6

Issue (6) : 504-521 https://doi.org/10.1007/s11515-011-1146-2

REVIEW

Hedgehog signaling: mechanisms and evolution

Xuan YE, Aimin LIU(

)

Department of Biology, Eberly College of Science, The Pennsylvania State University, University Park, PA 16802, USA

Download: PDF(689 KB) HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

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.

Keywords Hedgehog Shh Ihh Dhh Cubitus interruptus (Ci) Gli1 Gli2 Gli3 Patched Smoothened Cilia Drosophila mouse signaling development evolution

Corresponding Author(s): LIU Aimin,Email:axl25@psu.edu

Issue Date: 01 December 2011

Cite this article:

Xuan YE,Aimin LIU. Hedgehog signaling: mechanisms and evolution[J]. Front Biol, 2011, 6(6): 504-521.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-011-1146-2
https://academic.hep.com.cn/fib/EN/Y2011/V6/I6/504

Fig.1 The Hedgehog family of proteins plays multiple roles in the development of and vertebrates. (A) A embryo are divided into 14 parasegments along its anterior/posterior axis. Cells immediately anterior to each parasegment boundary express a transcription factor Cubitus interruptus (Ci), a secreted signaling molecule Wingless (Wg) and a Hedgehog (Hh) receptor Patched (Ptc). Cells immediately posterior to each parasegment boundary express a transcription factor Engrailed (En), an Hh, and a Wg receptor Frizzled (Fz). Hh and Wg maintain each other’s expression by activating Ci and En, respectively. This reciprocal signaling stabilizes the parasegment boundaries and ensures proper patterning in each parasegment. (B) Cells in the wing imaginal discs, primordia for the fly wing, are segregated into anterior (A) and posterior (P) compartments. En maintains Hh expression in the P compartment, which in turn activates expression in cells immediately anterior to the A/P compartment boundary. The expression of and () is also induced in anterior cells near the compartment boundary. (C) In the vertebrate spinal cord, Shh produced by notochord (N) and floorplate (F) forms a ventral-to-dorsal concentration gradient. Neural progenitor cells in the spinal cord adopt various interneuron (p0, p1, p2 and p3) and motor neuron (pMN) fates depending on the level of Shh signaling they receive. These neural progenitors later differentiate into mature neurons (v0, v1, v2, MN and v3) in a stereotypical pattern. The formation of the floorplate itself is dependent on the highest level of Shh activity. R: roofplate. (D) In vertebrate limb buds, Shh produced in the zone of polarizing activity (ZPA) is critical for patterning the digits along the anterior/posterior axis. The first digit in each limb (thumb or big toe) is the only digit that is independent of Shh.

Drosophila	Vertebrates	Roles in Hh signaling
Hedgehog (Hh)	Sonic, Indian and Desert hedgehog (Shh, Ihh and Dhh)	Ligands
Skinny hedgehog (Ski)	Skinny hedgehog (Skn)	Transmembrane acyltransferase critical for the palmitoylation of Hh proteins.
Dispatched (Disp)	Dispatched1 (Disp1)	A 12-pass transmembrane protein mediating the release of Hh-Np from Hh-producing cells
Apolipophorins (ApoLI and ApoLII)	Low density lipoprotein (LDL)	Form lipoprotein particles with Hh-Np and facilitate the long-range distribution of Hh in Drosophila. Roles unclear in vertebrates
Megalin	Megalin	An LDL receptor-related protein interacting with Shh in vertebrates, but not in Drosophila
Dally and Dally-like protein (Dlp)	Glypicans (Glp1-6)	GPI-linked heparan sulfate proteoglycans required for long-range Hh signaling and Hh reception in Drosophila. In vertebrates, they appear to limit the range of Hh signaling.
Tout-velu (Ttv)	Exostosin 1 (Ext1)	A glycosyltransferase required for glypican maturation. Facilitate long-range Hh signaling in Drosophila, but limit long-range Hh signaling in vertebrates.
Smoothened (Smo)	Smoothened (Smo)	A seven-pass transmembrane protein structurally related to G protein-coupled receptors, essential for Hh signal transduction
Patched (Ptc)	Patched (Ptch1 and 2)	12-pass transmembrane proteins and the receptors for Hh proteins.
Interfering hedgehog (Ihog)/Brother of Ihog (Boi)	Cdo/Brother of Cdo (Boc)	Immunoglobulin/fibronectin superfamily of transmembrane proteins interacting with Hh proteins and playing important roles in Hh reception and distribution.
--------	Growth arrest specific 1 (Gas1)	A GPI-linked Hh-interacting protein with a positive role in mammalian Hh signaling. No Drosophila homolog identified
--------	Hedgehog interacting protein (Hhip1)	A Hh-interacting transmembrane protein with a negative role in Hh signaling. No Drosophila homolog identified
Cubitus interruptus (Ci)	Glioma-associated homologs (Gli1, 2, 3)	Bipartite transcription factors (except for Gli1) mediating all transcriptional responses of Hh signaling.
Costal 2 (Cos2)	Kif7 and Kif27	Kinesin-like proteins. Both Cos2 and Kif7 are involved in Hh signaling and physically interact with Smo and Ci/Gli proteins. Kif27 is involved in motile cilia biogenesis
Fused (Fu)	Fused (Fu)	A serine/threonine kinase, part of a Ci-containing complex important for Hh signaling in Drosophila. In vertebrates, it is important for motile cilia biogenesis
Suppressor of fused (Sufu)	Suppressor of fused (Sufu)	A cytoplasmic protein directly interacting with Ci/Gli proteins. An essential negative regulator of Hh signaling in vertebrates, but dispensable in Drosophila.
Hedgehog-induced Math and BTB domain-containing protein (Hib)	Speckle type POZ protein (Spop)	Part of a ubiquitin ligase complex involved in the proteasomal degradation of Ci/Gli proteins
Supernumerary limbs (Slimb)	β-Transducin repeat containing protein (β-TrCP)	Part of a ubiquitin ligase complex involved in the proteolytic processing of Ci/Gli proteins
cAMP-dependent protein kinase (PKA)/casein kinase I (CKI)	cAMP-dependent protein kinase (PKA)/Casein Kinase I (CKI)	Serine-threonine kinases involved in the activation of Smo and proteolytic processing of Ci/Gli protein in both Drosophila and vertebrates
Glycogen synthase kinase 3 (Gsk3)	Glycogen synthase kinase 3 (Gsk3)	A serine-threonine kinase involved in the proteolytic processing of Ci/Gli protein in both Drosophila and vertebrates
Gαi	Gαi	A subunit of a trimeric G protein complex involved in Hh signaling downstream of Smo in Drosophila. Its involvement in vertebrates is unclear
--------	Protein phosphatases (PP4 and PP2a)	PP4 mediates the dephosphorylation of Smo and PP2a mediates the dephosphorylation of Gli proteins
--------	Pias1	An E3 ubiquitin ligase mediating SUMOylation of Gli proteins
--------	HDAC1	A deacetylase mediating the deacetylation of Gli1 and Gli2

Tab.1 The Hh pathway components and their roles in fruit flies and vertebrates

Fig.2 Hedgehog signaling pathway in . In the absence of Hedgehog (Hh), Patched (Ptc) inhibits the activity and cell surface localization of Smoothened (Smo). The transcription factor Ci forms a complex with Cos2, Fu and Sufu. Cos2 promotes the phosphorylation and subsequent Slimb/Cul1-mediated proteolytic processing of Ci by recruiting PKA, CKI and GSK3β. The processed Ci (CiR) enters the nucleus to repress the Hh target genes.
In Hh-producing cells, the Hh protein undergoes autoproteolysis during which the N-terminal half of the protein (Hh-N) is modified with cholesterol. Hh-N is palmitoylated through the function of an acyltransferase Skinny Hedgehog (Ski). The fully processed Hh (Hh-Np) is released into extracellular space through the function of Dispatched (Disp). The spread of Hh-Np is aided by the formation of a multimeric complex with lipophorin and interaction with GPI-linked heparan sulfate proteoglycans Dally and Dally-like protein (Dlp). Tout-velu (Ttv), a glycosyltransferase catalyzing the maturation of Dally/Dlp, is critical for long-range Hh signaling.
In Hh-receiving cells, Ihog/Boi and Dlp interact with Hh and facilitate the inactivation of Ptc by Hh. Smo is translocated to the cell surface and activates Ci through direct interaction with Cos2. The activation of Smo involves PKA and CKI-mediated phosphorylation of Smo, as well as the phosphorylation of Cos2, Fu and Sufu. Activated Ci (CiA) enters the nucleus, possibly together with Sufu, to activate Hh target genes. CiA is highly unstable owing to HIB/Cul3-mediated proteasomal degradation.

Fig.3 Sonic hedgehog signaling pathway in vertebrates. In the absence of Sonic hedgehog (Shh), Ptc1, but not Smo, is accumulated in the ciliary membrane. Gli2 and Gli3 proteins (Gli2/3), associated with Sufu, are phosphorylated by PKA/CKI/GSK3 and proteolytically processed into Gli2/3R. Gli2/3 and Sufu are not efficiently translocated to the cilia, possibly due to high PKA activity in the cell.
In Shh-producing cells, Shh undergoes autoproteolysis, cholesterol and palmitate dual modification to form processed Shh-Np. Disp is required for the release of Shh-Np, which is assembled into a multimeric protein complex. Glypicans homologous to Dally/Dlp interact with Shh (as well as Ihh), and limit the range of Shh signaling.
In Shh-receiving cells, Shh binds to Ptch1 and induces its internalization. Other cell surface proteins, such as Hhip1, Gas1, Glypican, Cdo/Boc (vertebrate homologs of Ihog/Boi), also interact with Shh. However, their localization and relationships with Ptch1 have not been investigated. Smo responds to Shh by trafficking into the cilia, a process facilitated by β-Arrestin, Kinesin and PKA. Shh also enhances the ciliary accumulation of Gli2/3 and Sufu, possibly by inhibiting PKA activity. Gli2/3 are activated in the cilia to form Gli2/3A and likely enter the nucleus without Sufu. Gli2/3A are unstable and subject to Spop/Cul3-mediated degradation.

Fig.4 The primary cilium.The primary cilium is present on almost every vertebrate cell. It consists of an axoneme enclosed in the ciliary membrane. The axoneme, with nine microtubule doublets arranged in a cartwheel pattern, grows out of a centriole at the base of the cilium. The centriole, comprising nine microtubule triplets, and proteins associated with it, form the basal body of the cilium. Intraflagellar transport (IFT) complex B and the trimeric kinesin 2 constitute the anterograde IFT system responsible for cargo trafficking to the top of the cilium. On the other hand, IFT complex A and cytoplasmic dynein carry out retrograde IFT, returning cargoes to the base of the cilium. BBSome, a multiprotein complex comprising seven Bardet-Biedl syndrome-related proteins, is localized to the pericentriolar material and the cilium. BBSome binds Rabin8, a Rab8-specific GDP/GTP exchange factor, and promotes Rab8 activation and ciliary membrane biogenesis. In addition, BBSome is recruited by Arl6 (BBS3)-GTP to form a membrane coat that targets certain transmembrane proteins (such as SSTR3) to the cilium. Septin located at the base of the ciliary membrane forms a barrier that is important for the separation between ciliary membrane and the rest of the plasma membrane.

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: 10.1016/S0092-8674(00)80094-X pmid:8706127
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: 10.1101/gad.1543607 pmid:17504941
3	Amanai K, Jiang J (2001). Distinct roles of central missing and dispatched in sending the Hedgehog signal. Development , 128(24): 5119–5127 pmid:11748147
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: 10.1038/ncb1210 pmid:15592457
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: 10.1074/jbc.M109.038232 pmid:19996099
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: 10.1016/S0092-8674(00)80292-5 pmid:9215627
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:12361967
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: 10.1016/S1534-5807(03)00394-0 pmid:14723851
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: 10.1242/jcs.060020 pmid:20016067
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: 10.1038/27932 pmid:9665133
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: 10.1242/dev.057950 pmid:21115611
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: 10.1016/S0960-9822(02)00480-3 pmid:8805249
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:7891723
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: 10.1016/S0092-8674(00)81677-3 pmid:10619433
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:11807029
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: 10.1242/dev.02217 pmid:16396909
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: 10.1002/dvdy.21926 pmid:19334287
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: 10.1038/ncb2013 pmid:20081843
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: 10.1016/j.devcel.2008.03.006 pmid:18477453
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: 10.1016/S0960-9822(02)01147-8 pmid:12372258
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: 10.1016/j.devcel.2007.03.004 pmid:17488627
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: 10.1126/science.1064437 pmid:11486055
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: 10.1016/S0092-8674(03)00199-5 pmid:12679031
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: 10.1101/gad.1025302 pmid:12414725
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: 10.1073/pnas.182542899 pmid:12391318
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: 10.1128/MCB.25.16.7042-7053.2005 pmid:16055716
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: 10.1101/gad.1185804 pmid:15075292
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: 10.1101/gad.1794109 pmid:19684112
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: 10.1073/pnas.95.5.2349 pmid:9482888
30	Chen Y, Struhl G (1996). Dual roles for patched in sequestering and transducing Hedgehog. Cell , 87(3): 553–563 doi: 10.1016/S0092-8674(00)81374-4 pmid:8898207
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: 10.1073/pnas.082096999 pmid:11960000
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: 10.1126/scisignal.2000405 pmid:19549984
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: 10.1006/dbio.2001.0346 pmid:11476582
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: 10.1038/383407a0 pmid:8837770
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: 10.1101/gad.1026303 pmid:12569124
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: 10.1038/17611 pmid:10050855
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: 10.1242/dev.02021 pmid:16155214
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: 10.1038/nature04117 pmid:16136078
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: 10.1371/journal.pone.0011996 pmid:20711444
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: 10.1186/1471-213X-5-21 pmid:16197551
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: 10.1016/S0092-8674(00)00056-8 pmid:10966113
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: 10.1242/dev.00874 pmid:14602684
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: 10.1016/S0960-9822(99)80482-5 pmid:10531011
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:9636069
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:11311154
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: 10.1016/j.cub.2009.06.046 pmid:19592253
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: 10.1186/1475-4924-1-10 pmid:12437772
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: 10.1016/j.cell.2009.03.023 pmid:19345185
49	Goodrich L V, Milenkovi? L, Higgins K M, Scott M P (1997). Altered neural cell fates and medulloblastoma in mouse patched mutants. Science , 277(5329): 1109–1113 doi: 10.1126/science.277.5329.1109 pmid:9262482
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: 10.1242/dev.00958 pmid:14729575
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: 10.1016/j.cub.2003.08.034 pmid:14521833
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: 10.1371/journal.pgen.0010053 pmid:16254602
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: 10.1016/0092-8674(93)90535-X pmid:8252627
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: 10.1002/dvdy.22130 pmid:19877275
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: 10.1016/j.cell.2006.03.002 pmid:16615888
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: 10.1016/0092-8674(89)90021-4 pmid:2582494
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: 10.1242/dev.029835 pmid:19004860
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: 10.1016/j.ydbio.2006.09.001 pmid:17027958
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: 10.1126/science.1191054 pmid:20558667
60	Huangfu D, Anderson K V (2005). Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci USA , 102(32): 11325–11330 doi: 10.1073/pnas.0505328102 pmid:16061793
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: 10.1038/nature02061 pmid:14603322
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: 10.1101/gad.1902910 pmid:20360384
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: 10.1242/dev.030015 pmid:19088085
65	Jia J, Kolterud A, Zeng H, Hoover A, Teglund S, Toftg?rd R, Liu A (2009b). Suppressor of Fused inhibits mammalian Hedgehog signaling in the absence of cilia. Dev Biol , 330(2): 452–460 doi: 10.1016/j.ydbio.2009.04.009 pmid:19371734
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: 10.1101/gad.1136603 pmid:14597665
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: 10.1038/nature03179 pmid:15616566
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: 10.1038/35154 pmid:9461217
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: 10.1016/j.cell.2010.05.015 pmid:20603001
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: 10.1242/dev.00178 pmid:12421714
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: 10.1242/dev.041392 pmid:19906846
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: 10.1126/science.1157983 pmid:18497258
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: 10.1016/j.devcel.2004.05.009 pmid:15177029
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: 10.1016/S0925-4773(00)00492-5 pmid:11118883
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: 10.1016/0092-8674(93)90628-4 pmid:8269519
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: 10.1016/S0960-9822(01)00323-2 pmid:11509241
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: 7985023" target="_blank">10.1126/science. pmid:7985023 pmid:7985023
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: 10.1158/0008-5472.CAN-06-0505 pmid:16849540
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: 10.1242/dev.01230 pmid:15215207
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: 10.1016/S0092-8674(01)00369-5 pmid:11389830
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: 10.1073/pnas.0600124103 pmid:16611729
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:19666503
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: 10.1038/79916 pmid:11017169
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: 10.1038/nature01033 pmid:12198547
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: 10.1242/dev.01894 pmid:15930098
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: 10.1126/science.1081403 pmid:12663920
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: 10.1016/S1097-2765(03)00426-X pmid:14636583
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: 10.1016/0092-8674(93)90536-Y pmid:8252628
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: 10.1016/S0092-8674(02)00977-7 pmid:12372301
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: 10.1038/384176a0 pmid:8906794
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: 10.1101/gad.1546307 pmid:17504940
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:9389670
93	Matise M P, Joyner A L (1999). Gli genes in development and cancer. Oncogene , 18(55): 7852–7859 doi: 10.1038/sj.onc.1203243 pmid:10630638
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: 10.1016/j.ydbio.2005.08.050 pmid:16229832
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: 10.1074/jbc.M201933200 pmid:11964399
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: 10.1038/nature07358 pmid:18794898
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: 10.1128/MCB.25.16.7054-7068.2005 pmid:16055717
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:10952898
99	Methot N, Basler K (2001). An absolute requirement for Cubitus interruptus in Hedgehog signaling. Development , 128(5): 733–742 pmid:11171398
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:11861468
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: 10.1083/jcb.200907126 pmid:19948480
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: 10.1101/gad.1966210 pmid:20889716
103	Nachury M V, Loktev A V, Zhang Q, Westlake C J, Per?nen 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: 10.1016/j.cell.2007.03.053 pmid:17574030
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: 10.1038/341508a0 pmid:2797178
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: 10.1093/hmg/ddp113 pmid:19286674
106	Nusslein-Volhard C, Wieschaus E (1980). Mutations affecting segment number and polarity in Drosophila. Nature , 287(5785): 795–801 doi: 10.1038/287795a0 pmid:6776413
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: 10.1038/ng1682 pmid:16311596
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: 10.1002/dvdy.21551 pmid:18488998
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: 10.1016/j.cub.2003.10.004 pmid:14614827
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: 10.1038/nature07459 pmid:18987629
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: 10.1038/nature05246 pmid:17086203
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: 10.1101/gad.4.6.1053 pmid:2166702
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: 10.1042/BJ20030786 pmid:14611647
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: 10.1128/MCB.26.9.3365-3377.2006 pmid:16611981
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: 10.1038/nature03504 pmid:15875013
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: 10.1038/ng1753 pmid:16493421
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: 10.1093/hmg/ddp075 pmid:19223390
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: 10.1006/dbio.1999.9335 pmid:10433824
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: 10.1074/jbc.273.22.14037 pmid:9593755
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: 10.1016/S0092-8674(00)80074-4 pmid:8689684
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: 10.1038/374363a0 pmid:7885476
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: 10.1126/science.274.5285.255 pmid:8824192
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:1468628
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:10477300
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: 10.1016/S0092-8674(02)00664-5 pmid:11955435
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: 10.1073/pnas.1011410108 pmid:21209331
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: 10.1126/science.1178712 pmid:19933103
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: 10.1016/S0092-8674(00)80331-1 pmid:9244297
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: 10.1016/0092-8674(95)90397-6 pmid:7736596
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: 10.1073/pnas.0813373106 pmid:19218434
132	Rohatgi R, Milenkovic L, Scott M P (2007). Patched1 regulates hedgehog signaling at the primary cilium. Science , 317(5836): 372–376 doi: 10.1126/science.1139740 pmid:17641202
133	Rohatgi R, Snell W J (2010). The ciliary membrane. Curr Opin Cell Biol , 22(4): 541–546 doi: 10.1016/j.ceb.2010.03.010 pmid:20399632
134	Rosenbaum J L, Witman G B (2002). Intraflagellar transport. Nat Rev Mol Cell Biol , 3(11): 813–825 doi: 10.1038/nrm952 pmid:12415299
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: 10.1038/ncb1052 pmid:14523402
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: 10.1016/j.cub.2003.09.025 pmid:14521834
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: 10.1016/j.ydbio.2006.02.050 pmid:16595130
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: 10.1016/S0092-8674(00)80332-3 pmid:9244298
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: 10.1101/gad.13.16.2072 pmid:10465785
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: 10.1038/384129a0 pmid:8906787
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:10564661
142	Svard J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergstr?m A, Ericson J, Toftg?rd 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: 10.1016/j.devcel.2005.12.013 pmid:16459298
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: 10.1016/0092-8674(94)90175-9 pmid:8287482
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: 10.1038/nature00989 pmid:12192414
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: 10.1242/dev.01606 pmid:15647323
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: 10.1016/j.devcel.2006.04.004 pmid:16647304
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: 10.1016/S1097-2765(00)80214-2 pmid:10549295
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: 10.1242/dev.01563 pmid:15576405
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: 10.1038/ng.105 pmid:18327258
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: 10.1083/jcb.201004108 pmid:20956384
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: 10.1016/j.devcel.2005.12.014 pmid:16459297
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: 10.1056/NEJMoa0905360 pmid:19726763
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: 10.1016/S0092-8674(00)80678-9 pmid:10693759
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: 10.1242/dev.052126 pmid:20463034
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: 10.1101/gad.843900 pmid:11090136
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: 10.1073/pnas.0812110106 pmid:19196978
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: 10.1128/MCB.01089-09 pmid:20154143
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: 10.1101/gad.1025702 pmid:12435628
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: 10.1073/pnas.1001777107 pmid:20231458
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: 10.1371/journal.pone.0005182 pmid:19365551
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: 10.1038/nature07883 pmid:19305393
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: 10.1016/j.neuron.2009.03.022 pmid:19447091
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: 10.1242/dev.045740 pmid:20501592
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: 10.1016/j.cell.2006.02.040 pmid:16630821
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: 10.1126/science.1179386 pmid:19726788
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: 10.1016/j.devcel.2010.06.007 pmid:20643350
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: 10.1242/dev.028464 pmid:19144723
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: 10.1016/j.ydbio.2010.01.003 pmid:20067783
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: 10.1371/journal.pone.0015900 pmid:21209912
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: 10.1038/35079648 pmid:11395778
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: 10.1073/pnas.0408093101 pmid:15598741
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: 10.1073/pnas.0912008106 pmid:19955409
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: 10.1016/j.devcel.2005.01.001 pmid:15691767
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: 10.1016/S0092-8674(01)00385-3 pmid:11517919
175	Zhao Y, Tong C, Jiang J (2007). Hedgehog regulates smoothened activity by inducing a conformational switch. Nature , 450(7167): 252–258 doi: 10.1038/nature06225 pmid:17960137
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: 10.1101/gad.1870310 pmid:20048000
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: 10.1101/gad.1080803 pmid:12730121

[1]	Vivek Vishnu Anasa, Palaniyandi Ravanan, Priti Talwar. Multifaceted roles of ASB proteins and its pathological significance[J]. Front. Biol., 2018, 13(5): 376-388.
[2]	Ailing Zhou,Song Han,Zhaolan Joe Zhou. Molecular and genetic insights into an infantile epileptic encephalopathy – CDKL5 disorder[J]. Front. Biol., 2017, 12(1): 1-6.
[3]	Rachel Babij,Natalia De Marco Garcia. Neuronal activity controls the development of interneurons in the somatosensory cortex[J]. Front. Biol., 2016, 11(6): 459-470.
[4]	Karen Arnaud,Ariel A. Di Nardo. Choroid plexus trophic factors in the developing and adult brain[J]. Front. Biol., 2016, 11(3): 214-221.
[5]	Fatih Semerci,Mirjana Maletic-Savatic. Transgenic mouse models for studying adult neurogenesis[J]. Front. Biol., 2016, 11(3): 151-167.
[6]	Rini Jacob,Anbalagan Moorthy. Targeting secret handshakes of biological processes for novel drug development[J]. Front. Biol., 2016, 11(2): 132-140.
[7]	Kai Jiang,Jianhang Jia. Smoothened regulation in response to Hedgehog stimulation[J]. Front. Biol., 2015, 10(6): 475-486.
[8]	Yicheng Ding,Linda Howard,Louise Gallagher,Sanbing Shen. Regulation and postsynaptic binding of neurexins – drug targets for neurodevelopmental and neuropsychiatric disorders[J]. Front. Biol., 2015, 10(3): 239-251.
[9]	Elaine Y. C. Hsia,Yirui Gui,Xiaoyan Zheng. Regulation of Hedgehog signaling by ubiquitination[J]. Front. Biol., 2015, 10(3): 203-220.
[10]	Yu Lu,Biao Yan,Xudong Liu,Yuchao Zhang,Shibi Zeng,Hao Hu,Rong Xiang,Yu Xu,Ying Yu,Xu Yang. Comparative study of oxidative stress induced by sand flower and schistose nanosized layered double hydroxides in N2a cells[J]. Front. Biol., 2015, 10(3): 279-286.
[11]	Meng WANG,Kasturi BANERJEE,Harriet BAKER,John W. CAVE. *Nucleotide sequence conservation of novel and established cis-regulatory sites within the tyrosine hydroxylase gene promoter*[J]. Front. Biol., 2015, 10(1): 74-90.
[12]	Gary R. HIME,Nicole SIDDALL,Katja HORVAY,Helen E. ABUD. Analyzing stem cell dynamics: use of cutting edge genetic approaches in model organisms[J]. Front. Biol., 2015, 10(1): 1-10.
[13]	Roshni S. RAINBOW,Heenam KWON,Li ZENG. The role of Nkx3.2 in chondrogenesis[J]. Front. Biol., 2014, 9(5): 376-381.
[14]	Vipul SHUKLA,Runqing LU. IRF4 and IRF8: governing the virtues of B lymphocytes[J]. Front. Biol., 2014, 9(4): 269-282.
[15]	Yaojuan LU,Longwei QIAO,Guanghua LEI,Ranim R. MIRA,Junxia GU,Qiping ZHENG. Col10a1 gene expression and chondrocyte hypertrophy during skeletal development and disease[J]. Front. Biol., 2014, 9(3): 195-204.

Viewed

Full text

Abstract

Cited

Shared

Discussed