{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T14:25:22Z","timestamp":1759587922310},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"16","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivations: The development of most tissues and organs relies on a limited number of signal transduction pathways enabling the coordination of cellular differentiation. A proper understanding of the roles of signal transduction pathways requires the definition of formal models capturing the main qualitative features of these patterning processes. This is a challenging task because the underlying processes, diffusion, regulatory modifications, reception and sequestration of signalling molecules, transcriptional regulation of target genes, etc. are only partly characterized. In this context, qualitative models can be more readily proposed on the basis of available (molecular) genetic data. But this requires novel computational tools and proper qualitative representations of phenomena such as diffusion or sequestration.<\/jats:p>\n               <jats:p>To assess the power and limits of a logical formalism in this context, we propose a multi-level model of the multi-cellular network involved in the definition of the anterior\u2013posterior boundary during the development of the wing disc of Drosophila melanogaster. The morphogen Hedgehog (Hh) is the inter-cellular signal coordinating this process. It diffuses from the posterior compartment of the disc to activate its pathway in cells immediately anterior to the boundary. In these boundary cells, the Hh gradient induces target genes in distinct domains as a function of the Hh concentration. One target of Hh signalling is the gene coding for the receptor Patched (Ptc), which sequesters Hh and impedes further diffusion, thereby refining the boundary.<\/jats:p>\n               <jats:p>Results: We have delineated a logical model of the patterning process defining the cellular anterior\u2013posterior boundary in the developing imaginal disc of Drosophila melanogaster. This model qualitatively accounts for the formation of a gradient of Hh, as well as for the transduction of this signal through a balance between the activatory (CiA) and inhibitory (CiR) products of the gene cubitus interruptus (ci). Wild-type and mutant simulations have been carried out to assess the coherence of the model with experimental data. Interestingly, our computational analysis provides novel insights into poorly understood processes such as the regulation of Ptc by CiR, the formation of a functional gradient of CiA across boundary cells, or yet functional En differences between anterior and posterior cells.<\/jats:p>\n               <jats:p>In conclusion, our model analysis demonstrates the flexibility of the logical formalism, enabling consistent qualitative representation of diffusion, sequestration and post-transcriptional regulatory processes within and between neighbouring cells.<\/jats:p>\n               <jats:p>Availability: An XML file containing the proposed model together with annotations can be downloaded from our website (http:\/\/gin.univ-mrs.fr\/GINsim\/), along with GINsim, a logical modelling and simulation software freely available to academic groups.<\/jats:p>\n               <jats:p>Contact: \u00a0thieffry@tagc.univ-mrs.fr<\/jats:p>","DOI":"10.1093\/bioinformatics\/btn266","type":"journal-article","created":{"date-parts":[[2008,8,9]],"date-time":"2008-08-09T13:08:02Z","timestamp":1218287282000},"page":"i234-i240","source":"Crossref","is-referenced-by-count":37,"title":["Logical modelling of the role of the Hh pathway in the patterning of the <i>Drosophila<\/i> wing disc"],"prefix":"10.1093","volume":"24","author":[{"given":"Aitor","family":"Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"1 Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto, Japan, 2INSERM U928 - TAGC, Campus Scientifique de Luminy, Marseille and 3CONTRAINTES Project, INRIA-Rocquencourt, Le Chesnay, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudine","family":"Chaouiya","sequence":"additional","affiliation":[{"name":"1 Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto, Japan, 2INSERM U928 - TAGC, Campus Scientifique de Luminy, Marseille and 3CONTRAINTES Project, INRIA-Rocquencourt, Le Chesnay, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denis","family":"Thieffry","sequence":"additional","affiliation":[{"name":"1 Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto, Japan, 2INSERM U928 - TAGC, Campus Scientifique de Luminy, Marseille and 3CONTRAINTES Project, INRIA-Rocquencourt, Le Chesnay, France"},{"name":"1 Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto, Japan, 2INSERM U928 - TAGC, Campus Scientifique de Luminy, Marseille and 3CONTRAINTES Project, INRIA-Rocquencourt, Le Chesnay, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2008,8,9]]},"reference":[{"key":"2023020210501143700_B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0022-5193(03)00035-3","article-title":"The topology of the regulatory interactions predicts the expression pattern of the segment polarity genes in Drosophila melanogaster","volume":"223","author":"Albert","year":"2003","journal-title":"J. Theor. Biol"},{"key":"2023020210501143700_B2","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/S1097-2765(00)00044-7","article-title":"Posttranscriptional regulation of smoothened is part of a selfcorrecting mechanism in the Hedgehog signaling system","volume":"6","author":"Alcedo","year":"2000","journal-title":"Mol. Cell"},{"key":"2023020210501143700_B3","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1242\/dev.00286","article-title":"Requirements for transcriptional repression and activation by engrailed in Drosophila embryos","volume":"130","author":"Alexandre","year":"2003","journal-title":"Development"},{"key":"2023020210501143700_B4","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1101\/gad.10.16.2003","article-title":"Transcriptional activation of hedgehog target genes in Drosophila is mediated directly by the cubitus interruptus protein, a member of the GLI family of zinc finger DNA-binding proteins","volume":"10","author":"Alexandre","year":"1996","journal-title":"Genes Dev"},{"key":"2023020210501143700_B5","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/S0092-8674(00)80292-5","article-title":"Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor","volume":"89","author":"Aza-Blanc","year":"1997","journal-title":"Cell"},{"key":"2023020210501143700_B6","first-page":"1168","article-title":"Embo Gold Medal 1999. Waiting periods, instructive signals and positional information","volume":"19","author":"Basler","year":"2000","journal-title":"EMBO J"},{"key":"2023020210501143700_B7","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/368208a0","article-title":"Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein","volume":"368","author":"Basler","year":"1994","journal-title":"Nature"},{"key":"2023020210501143700_B8","first-page":"21","article-title":"engrailed expression in the anterior lineage compartment of the developing wing blade of","volume":"115","author":"Blair","year":"1992","journal-title":"Drosophila. Development"},{"key":"2023020210501143700_B9","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1371\/journal.pone.0000602","article-title":"Robustness and stability of the gene regulatory network involved in dv boundary formation in the drosophila wing","volume":"2","author":"Buceta","year":"2007","journal-title":"PLoS ONE"},{"key":"2023020210501143700_B10","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/j.1460-2075.1994.tb06236.x","article-title":"The Drosophila segment polarity gene patched interacts with decapentaplegic in wing development","volume":"13","author":"Capdevila","year":"1994","journal-title":"EMBO J"},{"key":"2023020210501143700_B11","first-page":"119","article-title":"Qualitative analysis of regulatory graphs:Acomputational tool based on a discrete formal framework","volume":"294","author":"Chaouiya","year":"2003","journal-title":"Lect. Notes Control Inf. Sci"},{"key":"2023020210501143700_B12","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0092-8674(00)81960-1","article-title":"Nuclear trafficking of Cubitus interruptus in the transcriptional regulation of Hedgehog target gene expression","volume":"98","author":"Chen","year":"1999","journal-title":"Cell"},{"key":"2023020210501143700_B13","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/S0092-8674(00)81374-4","article-title":"Dual roles for patched in sequestering and transducing Hedgehog","volume":"87","author":"Chen","year":"1996","journal-title":"Cell"},{"key":"2023020210501143700_B14","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1073\/pnas.95.5.2349","article-title":"Protein kinase A directly regulates the activity and proteolysis of cubitus interruptus","volume":"95","author":"Chen","year":"1998","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023020210501143700_B15","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.1242\/dev.121.10.3467","article-title":"groucho and hedgehog regulate engrailed expression in the anterior compartment of the Drosophila wing","volume":"121","author":"Celis","year":"1995","journal-title":"Development"},{"key":"2023020210501143700_B16","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0092-8674(00)00056-8","article-title":"Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened","volume":"102","author":"Denef","year":"2000","journal-title":"Cell"},{"key":"2023020210501143700_B17","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1126\/science.272.5268.1621","article-title":"Sending and receiving the hedgehog signal: control by the Drosophila Gli protein Cubitus interruptus","volume":"272","author":"Dominguez","year":"1996","journal-title":"Science"},{"key":"2023020210501143700_B18","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1101\/gad.4.6.1068","article-title":"Repression of ci-D in posterior compartments of Drosophila by engrailed","volume":"4","author":"Eaton","year":"1990","journal-title":"Genes Dev"},{"key":"2023020210501143700_B19","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.1101\/gad.10.22.2935","article-title":"araucan and caupolican provide a link between compartment subdivisions and patterning of sensory organs and veins in the drosophila wing","volume":"10","author":"G\u00f3mez-Skarmeta","year":"1996","journal-title":"Genes Dev"},{"key":"2023020210501143700_B20","first-page":"91","article-title":"Dynamical analysis of the regulatory network defining the dorsal-ventral boundary of the drosophila wing imaginal disc. Genetics. Gonz\u00e1lez,A. et al. (2006) GINsim: A software suite for the qualitative modelling, simulation and analysis of regulatory networks","volume":"84","author":"Gonz\u00e1lez","year":"2006","journal-title":"Biosystems"},{"key":"2023020210501143700_B21","doi-asserted-by":"crossref","first-page":"3447","DOI":"10.1242\/dev.121.10.3447","article-title":"The function of engrailed and the specification of Drosophila wing pattern","volume":"121","author":"Guillen","year":"1995","journal-title":"Development"},{"key":"2023020210501143700_B22","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1242\/dev.01689","article-title":"Differential regulation of Hedgehog target gene transcription by Costal2 and Suppressor of Fused","volume":"132","author":"Ho","year":"2005","journal-title":"Development"},{"key":"2023020210501143700_B23","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/nrm1622","article-title":"Communicating with Hedgehogs","volume":"6","author":"Hooper","year":"2005","journal-title":"Nat. Rev. Mol Cell Biol"},{"key":"2023020210501143700_B24","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/S0960-9822(95)00084-4","article-title":"Quantitative effects of hedgehog and decapentaplegic activity on the patterning of the Drosophila wing","volume":"5","author":"Ingham","year":"1995","journal-title":"Curr. Biol"},{"key":"2023020210501143700_B25","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1101\/gad.1136603","article-title":"Smoothened transduces Hedgehog signal by physically interacting with Costal2\/Fused complex through its C-terminal tail","volume":"17","author":"Jia","year":"2003","journal-title":"Genes Dev"},{"key":"2023020210501143700_B26","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1038\/nature03179","article-title":"Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I","volume":"432","author":"Jia","year":"2004","journal-title":"Nature"},{"key":"2023020210501143700_B27","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/0092-8674(95)90510-3","article-title":"Protein kinase A and hedgehog signaling in Drosophila limb development","volume":"80","author":"Jiang","year":"1995","journal-title":"Cell"},{"key":"2023020210501143700_B28","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/373711a0","article-title":"Signal transduction by cAMP-dependent protein kinase A in Drosophila limb patterning","volume":"373","author":"Lepage","year":"1995","journal-title":"Nature"},{"key":"2023020210501143700_B29","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/0092-8674(95)90509-X","article-title":"Function of protein kinase A in hedgehog signal transduction and Drosophila imaginal disc development","volume":"80","author":"Li","year":"1995","journal-title":"Cell"},{"key":"2023020210501143700_B30","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/dvdy.20617","article-title":"Establishment and maintenance of planar epithelial cell polarity by asymmetric cadherin bridges: a computer model","volume":"235","author":"Le Garrec","year":"2006","journal-title":"Dev. Dyn"},{"key":"2023020210501143700_B31","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/S0960-9822(01)00178-6","article-title":"The sterol-sensing domain of Patched protein seems to control Smoothened activity through Patched vesicular trafficking","volume":"11","author":"Mart\u00edn","year":"2001","journal-title":"Curr. Biol"},{"key":"2023020210501143700_B32","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1515\/znc-1980-11-1237","article-title":"Cooperation of compartments for the generation of positional information","volume":"35","author":"Meinhardt","year":"1980","journal-title":"Z. Naturforsch. C"},{"key":"2023020210501143700_B33","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/S0092-8674(00)80592-9","article-title":"Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus","volume":"96","author":"M\u00e9thot","year":"1999","journal-title":"Cell"},{"key":"2023020210501143700_B34","doi-asserted-by":"crossref","first-page":"2999","DOI":"10.1242\/dev.127.14.2999","article-title":"The repressor and activator forms of cubitus interruptus control hedgehog target genes through common generic gli-binding sites","volume":"127","author":"Muller","year":"2000","journal-title":"Development"},{"key":"2023020210501143700_B35","first-page":"749","article-title":"Decision diagrams for the representation and analysis of logical models of genetic networks. In Computational Methods in Systems Biology. Ohlmeyer,J.T. and Kalderon,D. (1998) Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator","volume":"396","author":"Naldi","year":"2007","journal-title":"Nature"},{"key":"2023020210501143700_B36","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.tcb.2006.02.004","article-title":"Hedgehog signalling: how to get from smo to ci and gli","volume":"16","author":"Osterlund","year":"2006","journal-title":"Trends Cell Biol"},{"key":"2023020210501143700_B37","doi-asserted-by":"crossref","first-page":"4331","DOI":"10.1242\/dev.126.19.4331","article-title":"Proteolysis of cubitus interruptus in Drosophila requires phosphorylation by Protein Kinase A","volume":"126","author":"Price","year":"1999","journal-title":"Development"},{"key":"2023020210501143700_B38","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/0925-4773(96)00498-4","article-title":"The fu gene discriminates between pathways to control dpp expression in Drosophila imaginal discs","volume":"55","author":"S\u00e1nchez-Herrero","year":"1996","journal-title":"Mech. Dev"},{"key":"2023020210501143700_B39","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1093\/genetics\/139.2.745","article-title":"Drawing a stripe in Drosophila imaginal disks: negative regulation of decapentaplegic and patched expression by","volume":"139","author":"Sanicola","year":"1995","journal-title":"engrailed. Genetics"},{"key":"2023020210501143700_B40","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1242\/dev.121.6.1625","article-title":"Analysis of cubitus interruptus regulation in Drosophila embryos and imaginal disks","volume":"121","author":"Schwartz","year":"1995","journal-title":"Development"},{"key":"2023020210501143700_B41","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.cub.2005.12.012","article-title":"Processing of the Drosophila hedgehog signaling effector Ci-155 to the repressor Ci-75 is mediated by direct binding to the SCF component slimb","volume":"16","author":"Smelkinson","year":"2006","journal-title":"Curr. Biol"},{"key":"2023020210501143700_B42","doi-asserted-by":"crossref","first-page":"4697","DOI":"10.1242\/dev.124.22.4697","article-title":"AHedgehog activity gradient contributes toAPaxial patterning of the Drosophila wing","volume":"124","author":"Strigini","year":"1997","journal-title":"Development"},{"key":"2023020210501143700_B43","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/S0960-9822(01)00179-8","article-title":"Mutations in the sterol-sensing domain of Patched suggest a role for vesicular trafficking in Smoothened regulation","volume":"11","author":"Strutt","year":"2001","journal-title":"Curr. Biol"},{"key":"2023020210501143700_B44","volume-title":"Biological feedback.","author":"Thomas","year":"1990"},{"key":"2023020210501143700_B45","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/BF02460618","article-title":"Dynamical behaviour of biological regulatory networks\u2013I. Biological role of feedback loops and practical use of the concept of the loopcharacteristic state","volume":"57","author":"Thomas","year":"1995","journal-title":"Bull. Math. Biol"},{"key":"2023020210501143700_B46","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1002\/(SICI)1521-1878(200005)22:5<460::AID-BIES8>3.0.CO;2-G","article-title":"hedgehog and wing development in Drosophila: a morphogen at work?","volume":"22","author":"Vervoort","year":"2000","journal-title":"Bioessays"},{"key":"2023020210501143700_B47","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/S0960-9822(99)80285-1","article-title":"The COE transcription factor Collier is a mediator of short-range Hedgehog-induced patterning of the Drosophila wing","volume":"9","author":"Vervoort","year":"1999","journal-title":"Curr. Biol"},{"key":"2023020210501143700_B48","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1073\/pnas.94.6.2404","article-title":"Hedgehog signaling regulates transcription through cubitus interruptus, a sequence-specific DNA binding protein","volume":"94","author":"Von Ohlen","year":"1997","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023020210501143700_B49","doi-asserted-by":"crossref","first-page":"2828","DOI":"10.1101\/gad.13.21.2828","article-title":"Protein kinase A antagonizes Hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus","volume":"13","author":"Wang","year":"1999","journal-title":"Genes Dev"},{"key":"2023020210501143700_B50","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1242\/dev.121.8.2265","article-title":"Sequential organizing activities of engrailed, hedgehog and decapentaplegic in the Drosophila wing","volume":"121","author":"Zecca","year":"1995","journal-title":"Development"},{"key":"2023020210501143700_B51","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1101\/gad.1080803","article-title":"Altered localization of Drosophila Smoothened protein activates Hedgehog signal transduction","volume":"17","author":"Zhu","year":"2003","journal-title":"Genes Dev"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/24\/16\/i234\/49052199\/bioinformatics_24_16_i234.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/24\/16\/i234\/49052199\/bioinformatics_24_16_i234.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T12:48:20Z","timestamp":1675342100000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/24\/16\/i234\/199471"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,8,9]]},"references-count":51,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2008,8,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btn266","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2008,8,15]]},"published":{"date-parts":[[2008,8,9]]}}}