Nusse R, Clevers H. Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985–99.
Briscoe J, Therond PP. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol. 2013;14:416–29.
Simon E, Aguirre-Tamaral A, Aguilar G, Guerrero I. Perspectives on intra- and intercellular trafficking of Hedgehog for tissue patterning. J Dev Biol. 2016;4:34.
Kornberg TB, Roy S. Cytonemes as specialized signaling filopodia. Development. 2014;141:729–36.
Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci. 2017;75(2):193–208.
Parchure A, Vyas N, Ferguson C, Parton RG, Mayor S. Oligomerization and endocytosis of Hedgehog is necessary for its efficient exovesicular secretion. Mol Biol Cell. 2015;26:4700–17.
Stanganello E, Hagemann AI, Mattes B, Sinner C, Meyen D, Weber S, et al. Filopodia-based Wnt transport during vertebrate tissue patterning. Nat Commun. 2015;6:5846.
Rojas-Rios P, Guerrero I, Gonzalez-Reyes A. Cytoneme-mediated delivery of hedgehog regulates the expression of bone morphogenetic proteins to maintain germline stem cells in Drosophila. PLoS Biol. 2012;10:e1001298.
Bischoff M, Gradilla AC, Seijo I, Andres G, Rodriguez-Navas C, Gonzalez-Mendez L, et al. Cytonemes are required for the establishment of a normal Hedgehog morphogen gradient in Drosophila epithelia. Nat Cell Biol. 2013;15:1269–81.
Sanders TA, Llagostera E, Barna M. Specialized filopodia direct long-range transport of SHH during vertebrate tissue patterning. Nature. 2013;497:628–32.
Gradilla AC, Gonzalez E, Seijo I, Andres G, Bischoff M, Gonzalez-Mendez L, et al. Exosomes as Hedgehog carriers in cytoneme-mediated transport and secretion. Nat Commun. 2014;5:5649.
Chen W, Huang H, Hatori R, Kornberg TB. Essential basal cytonemes take up Hedgehog in the Drosophila wing imaginal disc. Development. 2017;144:3134–44.
Gonzalez-Mendez L, Seijo-Barandiaran I, Guerrero I. Cytoneme-mediated cell-cell contacts for Hedgehog reception. elife. 2017;6:e24045.
Port F, Basler K. Wnt trafficking: new insights into Wnt maturation, secretion and spreading. Traffic. 2010;11:1265–71.
Muller P, Schier AF. Extracellular movement of signaling molecules. Dev Cell. 2011;21:145–58.
Stanganello E, Scholpp S. Role of cytonemes in Wnt transport. J Cell Sci. 2016;129:665–72.
Elsum I, Yates L, Humbert PO, Richardson HE. The Scribble-Dlg-Lgl polarity module in development and cancer: from flies to man. Essays Biochem. 2012;53:141–68.
Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 2003;423:448–52.
Takada R, Satomi Y, Kurata T, Ueno N, Norioka S, Kondoh H, et al. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev Cell. 2006;11:791–801.
Rios-Esteves J, Resh MD. Stearoyl CoA desaturase is required to produce active, lipid-modified Wnt proteins. Cell Rep. 2013;4:1072–81.
Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC. Structural basis of Wnt recognition by Frizzled. Science. 2012;337:59–64.
Kumar S, Zigman M, Patel TR, Trageser B, Gross JC, Rahm K, et al. Molecular dissection of Wnt3a-Frizzled8 interaction reveals essential and modulatory determinants of Wnt signaling activity. BMC Biol. 2014;12:44.
Couso JP, Martinez AA. Notch is required for wingless signaling in the epidermis of Drosophila. Cell. 1994;79:259–72.
Nusse R. Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface. Development. 2003;130:5297–305.
Kakugawa S, Langton PF, Zebisch M, Howell S, Chang TH, Liu Y, et al. Notum deacylates Wnt proteins to suppress signalling activity. Nature. 2015;519:187–92.
Madan B, Ke Z, Lei ZD, Oliver FA, Oshima M, Lee MA, et al. NOTUM is a potential pharmacodynamic biomarker of Wnt pathway inhibition. Oncotarget. 2016;7:12386–92.
Komekado H, Yamamoto H, Chiba T, Kikuchi A. Glycosylation and palmitoylation of Wnt-3a are coupled to produce an active form of Wnt-3a. Genes Cells. 2007;12:521–34.
Mason JO, Kitajewski J, Varmus HE. Mutational analysis of mouse Wnt-1 identifies two temperature-sensitive alleles and attributes of Wnt-1 protein essential for transformation of a mammary cell line. Mol Biol Cell. 1992;3:521–33.
Chen X, Tukachinsky H, Huang CH, Jao C, Chu YR, Tang HY, et al. Processing and turnover of the Hedgehog protein in the endoplasmic reticulum. J Cell Biol. 2011;192:825–38.
Huang CH, Hsiao HT, Chu YR, Ye Y, Chen X. Derlin2 protein facilitates HRD1-mediated retro-translocation of sonic hedgehog at the endoplasmic reticulum. J Biol Chem. 2013;288:25330–9.
Porter JA, Ekker SC, Park WJ, von Kessler DP, Young KE, Chen CH, et al. Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. Cell. 1996;86:21–34.
Lee JJ, Ekker SC, von Kessler DP, Porter JA, Sun BI, Beachy PA. Autoproteolysis in hedgehog protein biogenesis. Science. 1994;266:1528–37.
Porter JA, Young KE, Beachy PA. Cholesterol modification of hedgehog signaling proteins in animal development. Science. 1996;274:255–9.
Buglino JA, Resh MD. Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog. J Biol Chem. 2008;283:22076–88.
Chamoun Z, Mann RK, Nellen D, von Kessler DP, Bellotto M, Beachy PA, et al. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science. 2001;293:2080–4.
Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, et al. Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem. 1998;273:14037–45.
Callejo A, Torroja C, Quijada L, Guerrero I. Hedgehog lipid modifications are required for Hedgehog stabilization in the extracellular matrix. Development. 2006;133:471–83.
Gallet A, Ruel L, Staccini-Lavenant L, Therond PP. Cholesterol modification is necessary for controlled planar long-range activity of Hedgehog in Drosophila epithelia. Development. 2006;133:407–18.
Palm W, Swierczynska MM, Kumari V, Ehrhart-Bornstein M, Bornstein SR, Eaton S. Secretion and signaling activities of lipoprotein-associated hedgehog and non-sterol-modified hedgehog in flies and mammals. PLoS Biol. 2013;11:e1001505.
Tokhunts R, Singh S, Chu T, D'Angelo G, Baubet V, Goetz JA, et al. The full-length unprocessed hedgehog protein is an active signaling molecule. J Biol Chem. 2010;285:2562–8.
Amanai K, Jiang J. Distinct roles of Central missing and Dispatched in sending the Hedgehog signal. Development. 2001;128:5119–27.
Burke R, Nellen D, Bellotto M, Hafen E, Senti KA, Dickson BJ, et al. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell. 1999;99:803–15.
Callejo A, Bilioni A, Mollica E, Gorfinkiel N, Andres G, Ibanez C, et al. Dispatched mediates Hedgehog basolateral release to form the long-range morphogenetic gradient in the Drosophila wing disk epithelium. Proc Natl Acad Sci U S A. 2011;108:12591–8.
Kawakami T, Kawcak T, Li YJ, Zhang W, Hu Y, Chuang PT. Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development. 2002;129:5753–65.
Ma Y, Erkner A, Gong R, Yao S, Taipale J, Basler K, et al. Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell. 2002;111:63–75.
Creanga A, Glenn TD, Mann RK, Saunders AM, Talbot WS, Beachy PA. Scube/You activity mediates release of dually lipid-modified Hedgehog signal in soluble form. Genes Dev. 2012;26:1312–25.
Hollway GE, Maule J, Gautier P, Evans TM, Keenan DG, Lohs C, et al. Scube2 mediates Hedgehog signalling in the zebrafish embryo. Dev Biol. 2006;294:104–18.
Kawakami A, Nojima Y, Toyoda A, Takahoko M, Satoh M, Tanaka H, et al. The zebrafish-secreted matrix protein you/scube2 is implicated in long-range regulation of hedgehog signaling. Curr Biol. 2005;15:480–8.
Tsai MT, Cheng CJ, Lin YC, Chen CC, Wu AR, Wu MT, et al. Isolation and characterization of a secreted, cell-surface glycoprotein SCUBE2 from humans. Biochem J. 2009;422:119–28.
Woods IG, Talbot WS. The you gene encodes an EGF-CUB protein essential for Hedgehog signaling in zebrafish. PLoS Biol. 2005;3:e66.
Jakobs P, Schulz P, Schurmann S, Niland S, Exner S, Rebollido-Rios R, et al. Ca(2+) coordination controls sonic hedgehog structure and its Scube2-regulated release. J Cell Sci. 2017;130:3261–71.
Avanesov A, Honeyager SM, Malicki J, Blair SS. The role of glypicans in Wnt inhibitory factor-1 activity and the structural basis of Wif1’s effects on Wnt and Hedgehog signaling. PLoS Genet. 2012;8:e1002503.
Bilioni A, Sanchez-Hernandez D, Callejo A, Gradilla AC, Ibanez C, Mollica E, et al. Balancing Hedgehog, a retention and release equilibrium given by Dally, Ihog, Boi and shifted/DmWif. Dev Biol. 2013;376:198–212.
Glise B, Miller CA, Crozatier M, Halbisen MA, Wise S, Olson DJ, et al. Shifted, the Drosophila ortholog of Wnt inhibitory factor-1, controls the distribution and movement of Hedgehog. Dev Cell. 2005;8:255–66.
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. 2005;8:241–53.
Lewis PM, Dunn MP, McMahon JA, Logan M, Martin JF, St-Jacques B, et al. Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell. 2001;105:599–612.
Gross JC, Chaudhary V, Bartscherer K, Boutros M. Active Wnt proteins are secreted on exosomes. Nat Cell Biol. 2012;14:1036–45.
Alexandre C, Baena-Lopez A, Vincent JP. Patterning and growth control by membrane-tethered Wingless. Nature. 2014;505:180–5.
D'Angelo G, Matusek T, Pizette S, Therond PP. Endocytosis of Hedgehog through dispatched regulates long-range signaling. Dev Cell. 2015;32:290–303.
Yamazaki Y, Palmer L, Alexandre C, Kakugawa S, Beckett K, Gaugue I, et al. Godzilla-dependent transcytosis promotes Wingless signalling in Drosophila wing imaginal discs. Nat Cell Biol. 2016;18:451–7.
Banziger C, Soldini D, Schutt C, Zipperlen P, Hausmann G, Basler K. Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell. 2006;125:509–22.
Bartscherer K, Pelte N, Ingelfinger D, Boutros M. Secretion of Wnt ligands requires Evi, a conserved transmembrane protein. Cell. 2006;125:523–33.
Goodman RM, Thombre S, Firtina Z, Gray D, Betts D, Roebuck J, et al. Sprinter: a novel transmembrane protein required for Wg secretion and signaling. Development. 2006;133:4901–11.
Yu J, Chia J, Canning CA, Jones CM, Bard FA, Virshup DM. WLS retrograde transport to the endoplasmic reticulum during Wnt secretion. Dev Cell. 2014;29:277–91.
Belenkaya TY, Han C, Yan D, Opoka RJ, Khodoun M, Liu H, et al. Drosophila Dpp morphogen movement is independent of dynamin-mediated endocytosis but regulated by the glypican members of heparan sulfate proteoglycans. Cell. 2004;119:231–44.
Franch-Marro X, Marchand O, Piddini E, Ricardo S, Alexandre C, Vincent JP. Glypicans shunt the Wingless signal between local signalling and further transport. Development. 2005;132:659–66.
Pan CL, Baum PD, Gu M, Jorgensen EM, Clark SG, Garriga G. C. elegans AP-2 and retromer control Wnt signaling by regulating mig-14/Wntless. Dev Cell. 2008;14:132–9.
Port F, Kuster M, Herr P, Furger E, Banziger C, Hausmann G, et al. Wingless secretion promotes and requires retromer-dependent cycling of Wntless. Nat Cell Biol. 2008;10:178–85.
Harterink M, Port F, Lorenowicz MJ, McGough IJ, Silhankova M, Betist MC, et al. A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion. Nat Cell Biol. 2011;13:914–23.
Pfeiffer S, Ricardo S, Manneville JB, Alexandre C, Vincent JP. Producing cells retain and recycle Wingless in Drosophila embryos. Curr Biol. 2002;12:957–62.
Strigini M, Cohen SM. Wingless gradient formation in the Drosophila wing. Curr Biol. 2000;10:293–300.
Yamamoto H, Awada C, Hanaki H, Sakane H, Tsujimoto I, Takahashi Y, et al. The apical and basolateral secretion of Wnt11 and Wnt3a in polarized epithelial cells is regulated by different mechanisms. J Cell Sci. 2013;126:2931–43.
Ayers KL, Gallet A, Staccini-Lavenant L, Therond PP. The long-range activity of Hedgehog is regulated in the apical extracellular space by the glypican Dally and the hydrolase Notum. Dev Cell. 2010;18:605–20.
Matusek T, Wendler F, Poles S, Pizette S, D'Angelo G, Furthauer M, et al. The ESCRT machinery regulates the secretion and long-range activity of Hedgehog. Nature. 2014;516:99–103.
Tabata T, Kornberg TB. Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell. 1994;76:89–102.
Bodeen WJ, Marada S, Truong A, Ogden SK. A fixation method to preserve cultured cell cytonemes facilitates mechanistic interrogation of morphogen transport. Development. 2017;144:3612–24.
Etheridge LA, Crawford TQ, Zhang S, Roelink H. Evidence for a role of vertebrate Disp1 in long-range Shh signaling. Development. 2010;137:133–40.
Ayers KL, Mteirek R, Cervantes A, Lavenant-Staccini L, Therond PP, Gallet A. Dally and Notum regulate the switch between low and high level Hedgehog pathway signalling. Development. 2012;139:3168–79.
He H, Huang M, Sun S, Wu Y, Lin X. Epithelial heparan sulfate regulates Sonic Hedgehog signaling in lung development. PLoS Genet. 2017;13:e1006992.
O'Farrell F, Lobert VH, Sneeggen M, Jain A, Katheder NS, Wenzel EM, et al. Class III phosphatidylinositol-3-OH kinase controls epithelial integrity through endosomal LKB1 regulation. Nat Cell Biol. 2017;19:1412–23.
Lobert VH, Stenmark H. Cell polarity and migration: emerging role for the endosomal sorting machinery. Physiology. 2011;26:171–80.
Chabu C, Li DM, Xu T. EGFR/ARF6 regulation of Hh signalling stimulates oncogenic Ras tumour overgrowth. Nat Commun. 2017;8:14688.
Steinhauer J, Liu HH, Miller E, Treisman JE. Trafficking of the EGFR ligand Spitz regulates its signaling activity in polarized tissues. J Cell Sci. 2013;126:4469–78.
Korkut C, Ataman B, Ramachandran P, Ashley J, Barria R, Gherbesi N, et al. Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless. Cell. 2009;139:393–404.
Beckett K, Monier S, Palmer L, Alexandre C, Green H, Bonneil E, et al. Drosophila S2 cells secrete wingless on exosome-like vesicles but the wingless gradient forms independently of exosomes. Traffic. 2013;14:82–96.
Beer KB, Wehman AM. Mechanisms and functions of extracellular vesicle release in vivo-What we can learn from flies and worms. Cell Adhes Migr. 2017;11:135–50.
Vyas N, Walvekar A, Tate D, Lakshmanan V, Bansal D, Lo Cicero A, et al. Vertebrate Hedgehog is secreted on two types of extracellular vesicles with different signaling properties. Sci Rep. 2014;4:7357.
Koles K, Nunnari J, Korkut C, Barria R, Brewer C, Li Y, et al. Mechanism of evenness interrupted (Evi)-exosome release at synaptic boutons. J Biol Chem. 2012;287:16820–34.
Ramirez-Weber FA, Kornberg TB. Cytonemes: cellular processes that project to the principal signaling center in Drosophila imaginal discs. Cell. 1999;97:599–607.
Cohen M, Georgiou M, Stevenson NL, Miodownik M, Baum B. Dynamic filopodia transmit intermittent Delta-Notch signaling to drive pattern refinement during lateral inhibition. Dev Cell. 2010;19:78–89.
De Joussineau C, Soule J, Martin M, Anguille C, Montcourrier P, Alexandre D. Delta-promoted filopodia mediate long-range lateral inhibition in Drosophila. Nature. 2003;426:555–9.
Hamada H, Watanabe M, Lau HE, Nishida T, Hasegawa T, Parichy DM, et al. Involvement of Delta/Notch signaling in zebrafish adult pigment stripe patterning. Development. 2014;141:318–24.
Huang H, Kornberg TB. Myoblast cytonemes mediate Wg signaling from the wing imaginal disc and Delta-Notch signaling to the air sac primordium. elife. 2015;4:e06114.
Peng Y, Han C, Axelrod JD. Planar polarized protrusions break the symmetry of EGFR signaling during Drosophila bract cell fate induction. Dev Cell. 2012;23:507–18.
Roy S, Hsiung F, Kornberg TB. Specificity of Drosophila cytonemes for distinct signaling pathways. Science. 2011;332:354–8.
Hsiung F, Ramirez-Weber FA, Iwaki DD, Kornberg TB. Dependence of Drosophila wing imaginal disc cytonemes on Decapentaplegic. Nature. 2005;437:560–3.
Roy S, Huang H, Liu S, Kornberg TB. Cytoneme-mediated contact-dependent transport of the Drosophila decapentaplegic signaling protein. Science. 2014;343:1244624.
Luz M, Spannl-Muller S, Ozhan G, Kagermeier-Schenk B, Rhinn M, Weidinger G, et al. Dynamic association with donor cell filopodia and lipid-modification are essential features of Wnt8a during patterning of the zebrafish neuroectoderm. PLoS One. 2014;9:e84922.
Couto A, Mack NA, Favia L, Georgiou M. An apicobasal gradient of Rac activity determines protrusion form and position. Nat Commun. 2017;8:15385.
Hagemann AI, Kurz J, Kauffeld S, Chen Q, Reeves PM, Weber S, et al. In vivo analysis of formation and endocytosis of the Wnt/beta-catenin signaling complex in zebrafish embryos. J Cell Sci. 2014;127:3970–82.
Bishop B, Aricescu AR, Harlos K, O'Callaghan CA, Jones EY, Siebold C. Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. Nat Struct Mol Biol. 2009;16:698–703.
Mii Y, Taira M. Secreted Wnt “inhibitors” are not just inhibitors: regulation of extracellular Wnt by secreted Frizzled-related proteins. Dev Growth Differentiation. 2011;53:911–23.
Georgiou M, Baum B. Polarity proteins and Rho GTPases cooperate to spatially organise epithelial actin-based protrusions. J Cell Sci. 2010;123:1089–98.
Ho HY, Rohatgi R, Lebensohn AM, Le M, Li J, Gygi SP, et al. Toca-1 mediates Cdc42-dependent actin nucleation by activating the N-WASP-WIP complex. Cell. 2004;118:203–16.
Snyder JC, Rochelle LK, Marion S, Lyerly HK, Barak LS, Caron MG. Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions. J Cell Sci. 2015;128:1230–40.
Carmon KS, Gong X, Yi J, Wu L, Thomas A, Moore CM, et al. LGR5 receptor promotes cell-cell adhesion in stem cells and colon cancer cells via the IQGAP1-Rac1 pathway. J Biol Chem. 2017;292:14989–5001.
Scopelliti A, Cordero JB, Diao F, Strathdee K, White BH, Sansom OJ, et al. Local control of intestinal stem cell homeostasis by enteroendocrine cells in the adult Drosophila midgut. Curr Biol. 2014;24:1199–211.
Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF. Vertebrate Smoothened functions at the primary cilium. Nature. 2005;437:1018–21.
Rohatgi R, Milenkovic L, Scott MP. Patched1 regulates hedgehog signaling at the primary cilium. Science. 2007;317:372–6.
Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet. 2005;1:e53.
Kornberg TB. The contrasting roles of primary cilia and cytonemes in Hh signaling. Dev Biol. 2014;394:1–5.
Yavari A, Nagaraj R, Owusu-Ansah E, Folick A, Ngo K, Hillman T, et al. Role of lipid metabolism in smoothened derepression in hedgehog signaling. Dev Cell. 2010;19:54–65.
Jiang K, Liu Y, Fan J, Zhang J, Li XA, Evers BM, et al. PI(4)P Promotes phosphorylation and conformational change of Smoothened through interaction with its C-terminal tail. PLoS Biol. 2016;14:e1002375.
Manikowski D, Kastl P, Grobe K. Taking the Ocam's Razor approach to Hedgehog lipidation and its role in development. J Dev Biol. 2018;6 https://doi.org/10.3390/jdb010003.
Cardozo MJ, Sanchez-Arrones L, Sandonis A, Sanchez-Camacho C, Gestri G, Wilson SW, et al. Cdon acts as a Hedgehog decoy receptor during proximal-distal patterning of the optic vesicle. Nat Commun. 2014;5:4272.
Sagar PF, Wiegreffe C, Scaal M. Communication between distant epithelial cells by filopodia-like protrusions during embryonic development. Development. 2015;142:665–71.
Huang YL, Niehrs C. Polarized Wnt signaling regulates ectodermal cell fate in Xenopus. Dev Cell. 2014;29:250–7.
Huang H, Kornberg TB. Cells must express components of the planar cell polarity system and extracellular matrix to support cytonemes. elife. 2016;5:e18979.
Hsia EYC, Zhang Y, Tran HS, Lim A, Chou YH, Lan G, et al. Hedgehog mediated degradation of Ihog adhesion proteins modulates cell segregation in Drosophila wing imaginal discs. Nat Commun. 2017;8:1275.