Communicating with hedgehogs

Nature Reviews Molecular Cell Biology

Volumn 6, Issue 4, 2005, Pages 306-317

  Hooper, Joan E ^a   Scott, Matthew P ^b  

^a UNIVERSITY OF COLORADO SCHOOL OF MEDICINE   (United States)

^b STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

SONIC HEDGEHOG PROTEIN;

BIOGENESIS; BIRTH DEFECT; CELL SURFACE; CYTOLOGY; DROSOPHILA MELANOGASTER; NONHUMAN; PRIORITY JOURNAL; PROTEIN LOCALIZATION; REVIEW; SIGNAL TRANSDUCTION;

DROSOPHILA MELANOGASTER; ERINACEIDAE; MELANOGASTER; METAZOA;

EID: 17144431776     PISSN: 14710072     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrm1622     Document Type: Review

References (120)

1. Reiter, C. & Gould, G. C. Thirteen ways of looking at a hedgehog. Natural History (American Museum of Natural History, New York, 1998).
2. Nusslein-Volhard, C. & Wieschaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 287, 795-801 (1980).
3. Krauss, S., Concordet, J. P. & Ingham, P. W. A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell 75, 1431-1444 (1993).
4. Riddle, R. D., Johnson, R. L., Laufer, E. & Tabin, C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75, 1401-1416 (1993).
5. Echelard, Y. et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417-1430 (1993).
6. Chang, D. T. et al. Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development 120, 3339-3353 (1994).
7. Roelink, H. et al. Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell 76, 761-775 (1994).
8. McMahon, A. P., Ingham, P. W. & Tabin, C. J. Developmental roles and clinical significance of hedgehog signaling. Curr. Top. Dev. Biol. 53, 1-114 (2003).
9. Baron, M. H. Embryonic origins of mammalian hematopoiesis. Exp. Hematol. 31, 1160-1169 (2003).
10. Machold, R. et al. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 39, 937-950 (2003).
11. Palma, V. & Ruiz i Altaba, A. Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development 131, 337-345 (2004).
12. Adolphe, C. et al. An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis. Development 131, 5009-5019 (2004).
13. Maye, p. et al. Hedgehog signaling is required for the differentiation of ES cells into neurectoderm. Dev. Biol. 265, 276-290 (2004).
14. Pasca di Magliano, M. & Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nature Rev. Cancer 3, 903-911 (2003).
15. Lum, L. & Beachy, P. A. The Hedgehog response network: sensors, switches, and routers. Science 304, 1755-1759 (2004).
16. Nusse, R. Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface. Development 130, 5297-5305 (2003).
17. Stegman, M. A. et al. The Kinesin-related protein Costal2 associates with membranes in a Hedgehog-sensitive, Smoothened-independent manner. J. Biol. Chem. 279, 7064-7071 (2004).
18. Bobbins, D. J. et al. Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein costal2. Cell 90, 225-234 (1997).
19. Sisson, J. C., Ho, K. S., Suyama, K. & Scott. M. P. Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway. Cell 90, 235-245 (1997).
20. Znang, W. et al. Hedgehog-regulated costal2-kinase complexes control phosphorylation and proteolytic processing of cubitus interruptus. Dev. Cell 8, 267-278 (2005). This paper shows how the kinesin-related protein Cos2 assembles a set of kinases that control Hh signalling by processing the transcription factor Ci.
21. Jiang, J. & Struhl, G. Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature 391, 493-496 (1998).
22. Dai, P., Akimaru, H. & Ishii, S. A hedgehog-responsive region in the Drosophila wing disc is defined by debra-mediated ubiquitination and lysosomal degradation of Ci. Dev. Cell 4, 917-926 (2003).
23. Lum, L. et al. Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2. Mol. Cell 12, 1261-1274 (2003). This is one of several papers (see also references 106-108) that connected the membrane protein Smo directly to the cytoplasmic kinesin-related protein Cos2, thereby bridging membrane events with the cytoplasmic protein complex.
24. Methot, N. & Basler, K. Suppressor of Fused opposes Hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus, Development 127, 4001-4210 (2000).
25. Cheng, S. Y. & Bishop, J. M. Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc. Natl Acad. Sci. USA 99, 5442-5447 (2002).
26. Merchant, M. et al. Suppressor of fused regulates Gli activity through a dual binding mechanism. Mol. Cell. Biol. 24, 8627-8641 (2004).
27. Jia, J., Tong, C., Wang, B., Luo, L. & Jiang, J. Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase 1. Nature 432, 1045-1050 (2005).
28. Apionishev, S., Katanayeva, N. M., Marks, S. A., Kalderon, D. & Tomlinson, A. Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction. Nature Cell Biol. 7, 86-92 (2005).
29. Zhang, C., Williams, E. H., Quo, Y., Lum, L. & Beachy, P. A, Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Proc. Natl Acad. Sci USA 101, 17900-17907 (2004).
30. Stegman, M. A. et al. Identification of a tetrameric hedgehog signaling complex. J. Biol. Chem. 275, 21809-21812 (2000).
31. Chen, C. H. et al. Nuclear trafficking of Cubitus interruptus in the transcriptional regulation of Hedgehog target gene expression. Cell 98, 305-316 (1999). Hh proteins are covalently joined to cholesterol at the C terminus and then to a palmitoyl group at the N terminus during their biosynthesis, which gives rise to a very greasy molecule. This paper reports an analysis of the importance of palmitoylation.
32. Kalderon, D. Transducing the hedgehog signal. Cell 103, 371-374 (2000).
33. Lee, J. D., Amanai, K., Shearn, A. & Treisman, J. E. The ubiquitin ligase Hyperpiastic discs negatively regulates hedgehog and decapentaplegic expression by independent mechanisms. Development 129, 5697-5706 (2002).
34. Ou, C. Y., Lin, Y. F., Chen, Y. J. & Chien, C. T. Distinct protein degradation mechanisms mediated by Cull and Cul3 controlling Ci stability in Drosophila eye development. Genes Dev. 16, 2403-2414 (2002).
35. Rahnama, F., Toftgard, R. & Zaphiropoulos, P. G. Distinct roles of PTCH2 splice variants in Hedgehog signalling. Biochem. J. 378, 325-334 (2004).
36. Kogerman, P. et al. Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nature Cell Biol. 1, 312-319 (1999).
37. Paces-Fessy, M., Boucher, D., Petit, E., Paute-Briand, S. & Blanchet-Tournier, M. F. The negative regulator of Gli. Suppressor of fused (Sufu), interacts with SAP18, Galectin3 and other nuclear proteins. Biochem. J. 378, 353-362 (2004).
38. Tay, S. Y., Ingham, P. W. & Roy, S. A homologue of the Drosophila kinesin-like protein Costal2 regulates Hedgehog signal transduction in the vertebrate embryo. Development 132, 625-634 (2005).
39. Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83-87 (2003). This paper contains the startling genetic evidence that proteins that transport substances within flagella and cilia are important for Hh signal transduction.
40. Callahan, C. A. et al. MIM/BEG4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription. Genes Dev. 18, 2724-2729 (2004). One of the newest components of Hh signalling, MIM, is a protein that binds to actin and regulates GLI activity.
41. McCarthy, R. A., Earth, J. L., Chintalapudi, M. R., Knaak, C. & Argraves, W. S. Megalin functions as an endocytic sonic hedgehog receptor. J. Biol. Chem. 277, 25660-25667 (2002).
42. Wolff, C. et al. iguana encodes a novel zinc-finger protein with coiled-coil domains essential for Hedgehog signal transduction in the zebrafish embryo. Genes Dev. 18, 1565-1576 (2004).
43. Sekimizu, K. et al. The zebrafish iguana locus encodes Dzip1, a novel zinc-finger protein required for proper regulation of Hedgehog signaling. Development 131, 2521-2532 (2004).
44. Bulgakov, O. V., Eggenschwiler, J. T., Hong, D. H., Anderson, K. V. & Li, T. FKBP8 is a negative regulator of mouse sonic hedgehog signaling in neural tissues. Development 131, 2149-2159 (2004).
45. Izraeli, S. et al. Genetic evidence that Sil is required for the Sonic Hedgehog response pathway. Genesis 31, 72-77 (2001).
46. Eggenschwiler, J. T., Espinoza, E. & Anderson, K. V. Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway. Nature 412, 194-198 (2001). A search for early mouse mutants led to the finding that Rab23 was a gene that was necessary for neuralation owing to its involvement in Hh signalling.
47. Glise, B. et al. Shifted, the Drosophila ortholog of wnt inhibitory factor-1, controls the distribution and movement of hedgehog. Dev. Cell 8, 255-266 (2005).
48. Gorfinkiel, N., Sierra, J., Callejo, A., Ibanez, C. & Guerrero, I. The Drosophila ortholog of the human wnt inhibitor factor shifted controls the diffusion of lipid-modified hedgehog. Dev. Cell 8, 241-253 (2005).
49. Han, C., Belenkaya, T. Y., Wang, B. & Lin, X. Drosophila glypicans control the cell-to-cell movement of Hedgehog by a dynamin-independent process. Development 131, 601-611 (2004).
50. Chuang, P. T. & McMahon, A. P. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397, 617-621 (1999).
51. Inaki, M., Kojima, T., Ueda, R. & Saigo, K. Requirements of high levels of Hedgehog signaling activity for medial-region cell fate determination in Drosophila legs: identification of pxb, a putative Hedgehog signaling attenuator gene repressed along the anterior-posterior compartment boundary. Mech. Dev. 116, 3-18 (2002).
52. Mullor, J. L. & Guerrero, I. A gain-of-function mutant of patched dissects different responses to the hedgehog gradient. Dev. Biol. 228, 211-224 (2000).
53. Strigini, M. & Cohen, S. M. A Hedgehog activity gradient contributes to AP axial patterning of the Drosophila wing. Development 124, 4697-4705 (1997).
54. Muller, B. & Basler, K. The repressor and activator forms of Cubitus interrupts control Hedgehog target genes through common generic Gli-binding sites. Development 127, 2999-3007 (2000).
55. Methot, N. & Basler, K. Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus. Cell 96, 819-831 (1999).
56. Bai, C. B., Stephen, D. & Joyner, A. L. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev. Cell 6, 103-115 (2004). This paper reports the most rigorous genetic study of the GLI proteins so far, which are the transcriptional regulators that are controlled by Hh signalling.
57. Lei, Q., Zelman, A. K., Kuang, E., Li, S. & Matise, M. P. Transduction of graded Hedgehog signaling by a combination of Gli2 and Gli3 activator functions in the developing spinal cord. Development 131, 3593-3604 (2004).
58. Wang, Q. T. & Holmgren, R. A. The subcellular localization and activity of Drosophila cubitus interruptus are regulated at multiple levels. Development 126, 5097-5106 (1999).
59. Mann, R. K. & Beachy, P. A. Novel lipid modifications of secreted protein signals. Annu. Rev. Biochem. 73, 891-923 (2004).
60. Peters, C., Wolf, A., Wagner, M., Kuhlmann, J. & Waldmann, H. The cholesterol membrane anchor of the Hedgehog protein confers stable membrane association tolipid-modified proteins. Proc. Natl Acad. Sci. USA 101, 8531-8536 (2004).
61. Burke, R. et al. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell 99, 803-815 (1999).
62. Kawakami, T. et al. Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development 129, 5753-5765 (2002).
63. Ma, Y. et al. Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 111, 63-75 (2002).
64. Tian, H., Tenzen, T. & McMahon, A. R Dose dependency of Disp1 and genetic interaction between Disp1 and other hedgehog signaling components in the mouse. Development 131, 4021-4033 (2004).
65. Zeng, X. et al. A freely diffusible form of Sonic hedgehog mediates long-range signalling. Nature 411, 716-720 (2001).
66. Chen, M. H., Li, Y. J., Kawakami, T., Xu, S. M. & Chuang, P. T. Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes Dev. 18. 641-659 (2004).
67. Feng, J. et al. Synergistic and antagonistic roles of the Sonic hedgehog N- and C-terminal lipids. Development 131, 4357-4370 (2004).
68. Denef, N., Neubuser, D., Perez, L. & Cohen, S. M. Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell 102, 521-531 (2000).
69. Incardona, J. P., Gruenberg, J. & Roelink, H. Sonic hedgehog induces the segregation of Patched and Smoothened in endosomes. Curr. Biol. 12, 893-895 (2002).
70. Gallet, A. & Therond, P. P. Temporal modulation of the Hedgehog morphogen gradient by a patched-dependent targeting to lysosomal compartment. Dev. Biol. 277, 51-62 (2005). A study of the fate of Hh protein after it enters the cell.
71. Torroja, C., Gorfinkiel, N. & Guerrero, I. Patched controls the Hedgehog gradient by endocytosis in a dynamin-dependent manner, but this internalization does not play a major role in signal transduction. Development 131, 2395-2408 (2004). This study of the intracellular locations and movements of Hh signal transduction components included the careful analysis of which events are important for Hh signalling.
72. Nybakken, K. & Perrimon, N. Hedgehog signal transduction: recent findings. Curr. Opin. Genet. Dev. 12, 503-511 (2002).
73. Desbordes, S. C. & Sanson, B. The glypican Dally-like is required for Hedgehog signalling in the embryonic epidermis of Drosophila. Development 130, 6245-6255 (2003).
74. Bornemann, D. J., Duncan, J. E., Staatz, W., Selleck, S. & Warrior, R. Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways. Development 131, 1927-1938 (2004). The mystery of how Hh proteins move between cells remains unsolved, but this paper provides evidence that heparan-sulphate proteoglycans are important for the movement of Hh and other signalling molecules in D. melanogaster.
75. Koziel, L., Kunath, M., Kelly, O. G. & Vortkamp, A. Ext1-dependent heparan sulfate regulates the range of lhh signaling during endochondral ossification. Cell Biol 6, 801-813 (2004).
76. Chen, Y. & Struhl, G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 87, 553-563 (1996).
77. Ioannou, Y. A. Multidrug permeases and subcellular cholesterol transport. Nature Rev. Mol. Cell Biol. 2, 657-668 (2001).
78. Taipale, J., Cooper, M. K., Maiti, T. & Beachy, P. A. Patched acts catalytically to suppress the activity of Smoothened. Nature 418, 892-897 (2002).
79. Ohgami, N. et al. Binding between the Niemann-Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain. Proc. Natl Acad. Sci. USA 101, 12473-12478 (2004).
80. Radhakrishnan, A., Sun, L. P., Kwon, H. J., Brown, M. S. & Goldstein, J. L. Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain. Mol. Cell 15, 259-268 (2004).
81. Kuwabara, P. E. & Labouesse, M. The sterol-sensing domain: multiple families, a unique role? Trends Genet. 18, 193-201 (2002).
82. Martin, V., Carrillo, G., Torroja, C. & Guerrero, I. The sterol-sensing domain of Patched protein seems to control Smoothened activity through Patched vesicular trafficking. Curr. Biol. 11, 601-607 (2001).
83. Strutt, H. et al. Mutations in the sterol-sensing domain of Patched suggest a role for vesicular trafficking in Smoothened regulation. Curr. Biol. 11, 608-613 (2001).
84. Johnson, R. L., Zhou, L. & Bailey, E. C. Distinct consequences of sterol sensor mutations in Drosophila and mouse patched homologs. Dev. Biol. 242, 224-235 (2002).
85. Ko, D. C., Gordon, M. D., Jin, J. Y. & Scott, M. P. Dynamic movements of organelles containing Niemann-Pick C1 protein: NPC1 involvement in late endocytic events. Mol. Biol. Cell 12, 601-614 (2001).
86. Davies, J. P., Chen, F. W. & Ioannou, Y. A. Transmembrane molecular pump activity of Niemann-Pick C1 protein. Science 290, 2295-2298 (2000).
87. Casali, A. & Struhl, G. Reading the Hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein. Nature 431, 76-80 (2004).
88. Hooper, J. E. Smoothened translates Hedgehog levels into distinct responses. Development 130, 3951-3963 (2003). This paper shows different, separable aspects of Smo function using chimeric constructs of Smo and its closest relative Fz, a Wnt receptor. A chimaera that consists of Fz on the outside and Smo on the inside of the cell responds to Wnt but triggers Hh signal transduction.
89. Stone, D. M. et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384, 129-134 (1996).
90. Johnson, R. L., Milenkovic, L. & Scott, M. P. In vivo functions of the patched protein: requirement of the C terminus for target gene inactivation but not Hedgehog sequestration. Mol. Cell 6, 467-478 (2000).
91. Zhu, A. J., Zheng, L., Suyama, K. & Scott, M. P. Altered localization of Drosophila Smoothened protein activates Hedgehog signal transduction. Genes Dev. 17, 1240-1252 (2003).
92. Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005-1009 (2000).
93. Chen, J. K., Taipale, J., Young, K. E., Maiti, T. & Beachy, P. A. Small molecule modulation of Smoothened activity. Proc. Natl Acad. Sci. USA 99, 14071-14076 (2002).
94. Chen, J. K., Taipale, J., Cooper, M. K. & Beachy, P. A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 16, 2743-2748 (2002).
95. Frank-Kamenetsky, M. et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J. Biol. 1, 10 (2002).
96. Evans, T. M., Ferguson, C., Wainwright, B. J., Partion, R. G. & Wicking, C. Rab23, a negative regulator of Hedgehog signaling, localizes to the plasma membrane and the endocytic pathway. Traffic 4, 869-884 (2003).
97. Nakano, Y. et al. Functional domains and sub-cellular distribution of the Hedgehog transducing protein Smoothened in Drosophila. Mech. Dev. 121, 507-518 (2004).
98. Eggenschwiler, J. T. & Anderson, K. V. Dorsal and lateral fates in the mouse neural tube require the cell-autonomous activity of the open brain gene. Dev. Biol. 227, 648-60 (2000).
99. Chen, W. et al. Activity-dependent internalization of smoothened mediated by β-arrestin 2 and GRK2. Science 306, 2257-2260 (2004).
100. Wilbanks, A. M. et al. β-arrestin 2 regulates zebrafish development through the hedgehog signaling pathway. Science 306, 2264-2267 (2004).
101. Richer, J. A., Freedman, N. J. & Lefkowitz, R. J. G protein-coupled receptor kinases. Annu. Rev. Biochem. 67, 653-6592 (1998).
102. Alcedo, J., Ayzenzon, M., Von Ohlen, T., Noll, M. & Hooper, J. E. The Drosophila Smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal. Cell 86, 221-232 (1996).
103. i-mediated signaling in frog melanophores. J. Biol. Chem. 275, 26322-26327 (2000).
104. Kasai, K. et al. The G12 family of heterotrimeric G proteins and Rho GTPase mediate Sonic hedgehog signalling. Genes Cells 9, 49-58 (2004).
105. Lum, L. et al. Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells. Science 299, 2039-2045 (2003). A large-scale screen that identified new Hh signal transduction components in D. melanogaster cultured cells, using RNAi.
106. Ogden, S. K. et al. Identification of a functional interaction between the transmembrane protein Smoothened and the kinesin-related protein Costal2. Curr. Biol. 13, 1998-2003 (2003).
107. Ruel, L., Rodriguez, R., Gallet, A., Lavenant-Staccini, L. & Therond, P. P. Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog. Nature Cell Biol. 5, 907-913 (2003).
108. Jia, J., Tong, C. & Jiang, J. Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its C-terminal tail. Genes Dev. 17, 2709-2720 (2003).
109. Ho, K. S., Suyama, K., Fish, M. & Scott, M. P. Differential regulation of Hedgehog target gene transcription by Costal2 and Suppressor of Fused. Development 132, 1401-1412 (2005).
110. Mahadevan, L. & Matsudaira, P. Motility powered by supramolecular springs and ratchets. Science 288, 95-100 (2000).
111. Kalderon, D. Similarities between the Hedgehog and Wnt signaling pathways. Trends Cell Biol. 12, 523-531 (2002).
112. Hall, T. M., Porter, J. A., Beachy, P. A. & Leahy, D. J. A potential catalytic site revealed by the 1.7-Å crystal structure of the amino-terminal signalling domain of Sonic hedgehog. Nature 378, 212-216 (1995).
113. Koonin, E. V. A protein splice-junction motif in hedgehog family proteins. Trends Biochem. Sci. 20, 141-142 (1995).
114. Hall, T. M. et al. Crystal structure of a Hedgehog autoprocessing domain: homology between Hedgehog and self-splicing proteins. Cell 91, 85-97 (1997).
115. Berman, D. M. et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297, 1559-1561 (2002).
116. -/- mice. Cancer Cell 6, 229-240 (2004). This paper analyses the effects of inhibitors of SMO on the growth of medulloblastomas, which are cranial tumours caused by the inadequate inhibition of Hh target gene activities. The results show both prevention of tumour formation and regression of pre-existing tumours.
117. Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Rev. Genet. 1, 20-29 (2000).
118. Shenoy, S. K. & Lefkowitz, R. J. Receptor-specific ubiquitination of β-arrestin directs assembly and targeting of 7TM receptor-signalosomes. J. Biol. Chem. 7 Feb 2005 [epub ahead of print].
119. Takei, Y., Ozawa, Y., Sato, M., Watanabe, A. & Tabata, T. Three Drosophila EXT genes shape morphogen gradients through synthesis of heparan sulfate proteoglycans. Development 131, 73-82 (2004).
120. Meng, X. et al. Suppressor offused negatively regulates β-catenin signaling. J. Biol. Chem. 276, 40113-40119 (2001).