{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T19:06:17Z","timestamp":1774897577039,"version":"3.50.1"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,1,14]],"date-time":"2019-01-14T00:00:00Z","timestamp":1547424000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2019,12]]},"DOI":"10.1186\/s12918-018-0672-9","type":"journal-article","created":{"date-parts":[[2019,1,14]],"date-time":"2019-01-14T12:23:04Z","timestamp":1547468584000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["An agent-based model of the Notch signaling pathway elucidates three levels of complexity in the determination of developmental patterning"],"prefix":"10.1186","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0655-4173","authenticated-orcid":false,"given":"Elaine R.","family":"Reynolds","sequence":"first","affiliation":[]},{"given":"Ryan","family":"Himmelwright","sequence":"additional","affiliation":[]},{"given":"Christopher","family":"Sanginiti","sequence":"additional","affiliation":[]},{"given":"Jeffrey O.","family":"Pfaffmann","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2019,1,14]]},"reference":[{"key":"672_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0070-2153(10)92001-2","volume":"92","author":"S Artavanis-Tsakonas","year":"2010","unstructured":"Artavanis-Tsakonas S, Muskavitch MAT. Notch: the past, the present and the future. Curr Top Dev Biol. 2010;92:1\u201329.","journal-title":"Curr Top Dev Biol"},{"key":"672_CR2","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1242\/dev.117.2.493","volume":"117","author":"PJ Kooh","year":"1993","unstructured":"Kooh PJ, Fehon RG, Muskavitch MAT. Implications of dynamic patterns of Delta and Notch expression for cellular interactions during Drosophila development. Development. 1993;117:493\u2013507.","journal-title":"Development"},{"key":"672_CR3","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1126\/science.7716513","volume":"268","author":"S Artavanis-Tsakonas","year":"1995","unstructured":"Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science. 1995;268:225\u201332.","journal-title":"Science"},{"key":"672_CR4","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.cell.2009.03.045","volume":"137","author":"R Kopan","year":"2009","unstructured":"Kopan R, Ilagan MXG. The canonical Notch Signaling pathway: unfolding the activation mechanism. Cell. 2009;137:216\u201333.","journal-title":"Cell"},{"key":"672_CR5","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1083\/jcb.200811141","volume":"184","author":"A-C Tien","year":"2009","unstructured":"Tien A-C, Rajan A, Bellen H. A Notch updated. J Cell Biol. 2009;184:621\u20139.","journal-title":"J Cell Biol"},{"key":"672_CR6","doi-asserted-by":"publisher","first-page":"1709","DOI":"10.1091\/mbc.9.7.1709","volume":"9","author":"K Klueg","year":"1998","unstructured":"Klueg K, Parody T, Muskavitch M. Complex proteolytic processing acts on Delta, a transmembrane ligand for Notch, during Drosophila development. Mol Biol Cell. 1998;9:1709\u201323.","journal-title":"Mol Biol Cell"},{"key":"672_CR7","doi-asserted-by":"publisher","first-page":"5367","DOI":"10.1242\/dev.01413","volume":"131","author":"W Wang","year":"2004","unstructured":"Wang W, Struhl G. Drosophila Epsin mediates a select endocytic pathway that DSL ligands must enter to activate Notch. Development. 2004;131:5367\u201380.","journal-title":"Development"},{"key":"672_CR8","doi-asserted-by":"publisher","first-page":"1751","DOI":"10.1242\/dev.01789","volume":"132","author":"RL Borgne","year":"2005","unstructured":"Borgne RL, Bardin A, Schweisguth F. The roles of receptor and ligand endocytosis in regulating Notch signaling. Development. 2005;132:1751\u201362.","journal-title":"Development"},{"key":"672_CR9","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1016\/j.yexcr.2008.09.010","volume":"315","author":"C Brou","year":"2009","unstructured":"Brou C. Intracellular trafficking of Notch receptors and ligands. Exp Cell Res. 2009;315:1549\u201355.","journal-title":"Exp Cell Res"},{"key":"672_CR10","doi-asserted-by":"crossref","first-page":"3283","DOI":"10.1242\/dev.124.17.3283","volume":"124","author":"SS Huppert","year":"1997","unstructured":"Huppert SS, Jacobsen TL, Muskavitch MAT. Feedback regulation is central to Delta-Notch signaling required for Drosophila wing vein morphogenesis. Development. 1997;124:3283\u201391.","journal-title":"Development"},{"key":"672_CR11","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1002\/dvg.20391","volume":"46","author":"AL Parks","year":"2008","unstructured":"Parks AL, Shalaby NA, Muskavitch MAT. Notch and suppressor of hairless regulate levels but not patterns of Delta expression in Drosophila. genesis. 2008;46:265\u201375.","journal-title":"genesis"},{"key":"672_CR12","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1126\/science.284.5415.770","volume":"284","author":"S Artavanis-Tsakonas","year":"1999","unstructured":"Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284:770\u20136.","journal-title":"Science"},{"key":"672_CR13","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1126\/science.1160617","volume":"322","author":"O Brandman","year":"2008","unstructured":"Brandman O, Meyer T. Feedback loops shape cellular signals in space and time. Science. 2008;322:390\u20135.","journal-title":"Science"},{"key":"672_CR14","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1083\/jcb.200203117","volume":"159","author":"K Mishra-Gorur","year":"2002","unstructured":"Mishra-Gorur K, Rand MD, Perez-Villamil B, Artavanis- Tsakonas S. Down-regulation of Delta by proteolytic processing. J Cell Biol. 2002;159:313\u201324.","journal-title":"J Cell Biol"},{"key":"672_CR15","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/150563a0","volume":"150","author":"C Waddington","year":"1942","unstructured":"Waddington C. Canalization of development and the inheritance of acquired characters. Nature. 1942;150:563\u20135.","journal-title":"Nature"},{"key":"672_CR16","doi-asserted-by":"publisher","first-page":"1654","DOI":"10.1038\/1831654a0","volume":"183","author":"C Waddington","year":"1959","unstructured":"Waddington C. Canalization of development and genetic assimilation of acquired characters. Nature. 1959;183:1654\u20135.","journal-title":"Nature"},{"key":"672_CR17","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1006\/jtbi.1996.0233","volume":"183","author":"JR Collier","year":"1996","unstructured":"Collier JR, Monk NAM, Maini PK, Lewis JH. Pattern formation by lateral inhibition with feedback: a mathematical model of Delta-Notch intercellular signaling. J Theor Biol. 1996;183:429\u201346.","journal-title":"J Theor Biol"},{"key":"672_CR18","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1006\/bulm.1999.0152","volume":"62","author":"H Wearing","year":"2000","unstructured":"Wearing H, Owen M, Sherratt J. Mathematical modeling of juxtacrine patterning. Bull Math Biol. 2000;62:293\u2013320.","journal-title":"Bull Math Biol"},{"key":"672_CR19","first-page":"329","volume":"2000","author":"G Marnellos","year":"2000","unstructured":"Marnellos G, Deblandre G, Mjolsness E, Kintner C. Delta-Notch lateral inhibitory patterning in the emergence of ciliated cells in Xenopus: experimental observations and a gene network model. Pac Symp Biocomput. 2000;2000:329\u201340.","journal-title":"Pac Symp Biocomput"},{"key":"672_CR20","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.biosystems.2005.10.003","volume":"84","author":"AG Gonzales","year":"2006","unstructured":"Gonzales AG, Naldi A, Sanchez L, Thieffry D, Chaouiya C. GINsim: a software suite for the qualitative modeling, simulation and analysis of regulatory networks. Biosystems. 2006;84:91\u2013100.","journal-title":"Biosystems"},{"key":"672_CR21","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1371\/journal.pcbi.0030092","volume":"3","author":"J Fisher","year":"2007","unstructured":"Fisher J, Piterman N, Hajnal A, Henzinger TA. Predictive modeling of signaling crosstalk during C. elegans vulval development. PLoS Comput Biol. 2007;3:862\u201373.","journal-title":"PLoS Comput Biol"},{"key":"672_CR22","doi-asserted-by":"crossref","unstructured":"Schaub MA, Henzinger TA, Fisher J. Qualitative networks: a symbolic approach to analyze biological signaling networks. BMC Syst Biol. 2007;1(4).","DOI":"10.1186\/1752-0509-1-4"},{"key":"672_CR23","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1007\/s00285-008-0178-y","volume":"57","author":"R Schlicht","year":"2008","unstructured":"Schlicht R, Winkler G. A delay stochastic process with applications in molecular biology. J Math Biol. 2008;57:613\u201348.","journal-title":"J Math Biol"},{"key":"672_CR24","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/978-1-4939-1139-4_22","volume-title":"Notch Signaling: methods and protocols. Methods in molecular biology","author":"P Formosa- Jordan","year":"2014","unstructured":"Formosa- Jordan P, Sprinzak D. Modeling Notch Signaling: a practical tutorial. In: Bellen HJ, Yamamoto S, editors. Notch Signaling: methods and protocols. Methods in molecular biology, vol. 1187. New York: Springer; 2014. p. 285\u2013310."},{"key":"672_CR25","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1126\/science.1193210","volume":"331","author":"Y Afek","year":"2011","unstructured":"Afek Y, Alon N, Barad O, Hornstein E, Barkai N, Bar-Joseph Z. A biological solution to a fundamental distributed computing problem. Science. 2011;331:183\u20135.","journal-title":"Science"},{"key":"672_CR26","volume-title":"Turtles, termites, and traffic jams: explorations in massively parallel microworlds","author":"M Resnick","year":"1994","unstructured":"Resnick M. Turtles, termites, and traffic jams: explorations in massively parallel microworlds. 1st ed. Cambridge: MIT Press; 1994.","edition":"1"},{"key":"672_CR27","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1162\/biot.2006.1.4.404","volume":"1","author":"W Griffin","year":"2006","unstructured":"Griffin W. Agent-based modeling for the theoretical biologist. Biol Theory. 2006;1:404\u20139.","journal-title":"Biol Theory"},{"key":"672_CR28","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1093\/bib\/bbp010","volume":"10","author":"DC Walker","year":"2009","unstructured":"Walker DC, Southgate J. The virtual cell--a candidate co-ordinator for \u2018middle-out\u2019 modelling of biological systems. Brief Bioinform. 2009;10:450\u201361.","journal-title":"Brief Bioinform"},{"key":"672_CR29","unstructured":"Wilensky U. Netlogo. Center for connected learning and computer-based modeling, Northwestern University 1999. http:\/\/ccl.northwestern.edu\/netlogo\/ . Accessed 27 Dec 2017."},{"key":"672_CR30","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1242\/dev.112.2.365","volume":"112","author":"Z Kam","year":"1991","unstructured":"Kam Z, Minden JS, Agard DA, Sedat JW, Leptin M. Drosophila gastrulation: analysis of cell shape changes in living embryos by three-dimensional fluorescence microscopy. Development. 1991;112:365\u201370.","journal-title":"Development"},{"key":"672_CR31","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.jtbi.2016.05.025","volume":"404","author":"SS Lee","year":"2016","unstructured":"Lee SS. Lateral inhibition-induced pattern formation controlled by the size and geometry of the cell. J Theor Biol. 2016;404:51\u201365.","journal-title":"J Theor Biol"},{"key":"672_CR32","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.neuron.2008.02.014","volume":"58","author":"H Shimojo","year":"2008","unstructured":"Shimojo H, Ohtsuka T, Kageyama R. Oscillations in Notch signaling regulate maintenance of neural progenitors. Neuron. 2008;58:52\u201364.","journal-title":"Neuron"},{"key":"672_CR33","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/978-1-4939-1139-4_13","volume-title":"Notch Signaling: methods and protocols. Methods in molecular biology","author":"H Shimojo","year":"2014","unstructured":"Shimojo H, Harima Y, Kageyama R. Visualization of Notch signaling oscillation in cells and tissues. In: Bellen HJ, Yamamoto S, editors. Notch Signaling: methods and protocols. Methods in molecular biology, vol. 1187. New York: Springer; 2014. p. 169\u201379."},{"key":"672_CR34","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1038\/nature05954","volume":"448","author":"G Dietzl","year":"2007","unstructured":"Dietzl G, Chen D, Schnorrer F, Su KC, Barinova Y, Fellner M, et al. A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature. 2007;448:151\u20136.","journal-title":"Nature"},{"key":"672_CR35","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/j.devcel.2010.03.013","volume":"18","author":"A Saj","year":"2010","unstructured":"Saj A, Arziman Z, Stempfle D, van Belle W, Sauder U, Horn T, et al. A combined ex vivo and in vivo RNAi screen for Notch regulators in Drosophila reveals an extensive Notch interaction network. Dev Cell. 2010;18:862\u201376.","journal-title":"Dev Cell"},{"key":"672_CR36","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4939-1139-4","volume-title":"Notch Signaling: Methods and protocols. Methods in molecular biology Vol 1187","author":"HJ Bellen","year":"2014","unstructured":"Bellen HJ, Yamamoto S. Notch Signaling: Methods and protocols. Methods in molecular biology Vol 1187. New York: Springer; 2014."},{"key":"672_CR37","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1083\/jcb.200310098","volume":"166","author":"N Gupta-Rossi","year":"2004","unstructured":"Gupta-Rossi N, Six E, LeBail O, Logeat F, Chastagner P, Olry A, et al. Monoubiquitination and endocytosis direct gamma-secretase cleavage of activated Notch receptor. J Cell Biol. 2004;166:73\u201383.","journal-title":"J Cell Biol"},{"key":"672_CR38","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1093\/embo-reports\/kvf124","volume":"3","author":"A Geling","year":"2002","unstructured":"Geling A, Steiner H, Willem M, Bally-Cuif L, Haass C. A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep. 2002;3:688\u201394.","journal-title":"EMBO Rep"},{"key":"672_CR39","doi-asserted-by":"publisher","first-page":"5399","DOI":"10.1242\/dev.00118","volume":"129","author":"SJ Eglen","year":"2002","unstructured":"Eglen SJ, Willshaw DJ. Influence of cell fate mechanisms upon retinal mosaic formation: a modeling study. Development. 2002;129:5399\u2013408.","journal-title":"Development"},{"key":"672_CR40","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/S0012-1606(03)00107-6","volume":"258","author":"NJ Savill","year":"2003","unstructured":"Savill NJ, Sherratt JA. Control of epidermal stem cell clusters by Notch-mediated lateral induction. Dev Biol. 2003;258:141\u201353.","journal-title":"Dev Biol"},{"key":"672_CR41","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.jtbi.2007.05.014","volume":"248","author":"HB Tiedemann","year":"2007","unstructured":"Tiedemann HB, Schneltzer E, Zeiser S, Rubio-Aliaga I, Wurst W, Beckers J, et al. Cell-based simulation of dynamic expression patterns in the presomitic mesoderm. J Theor Biol. 2007;248:120\u20139.","journal-title":"J Theor Biol"},{"key":"672_CR42","doi-asserted-by":"publisher","first-page":"e1004591","DOI":"10.1371\/journal.pcbi.1004591","volume":"12","author":"E Bartocci","year":"2016","unstructured":"Bartocci E, Li\u00f3 P. Computational modeling, formal analysis, and tools for systems biology. PLoS Comput Biol. 2016;12:e1004591. https:\/\/doi.org\/10.1371\/journal.pcbi.1004591 .","journal-title":"PLoS Comput Biol"},{"key":"672_CR43","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1093\/bib\/bbp073","volume":"11","author":"P Richmond","year":"2010","unstructured":"Richmond P, Walker DC, Coakley S, Romano DM. High performance cellular level agent-based simulation with FLAME for the GPU. Brief Bioinform. 2010;11:334\u201347.","journal-title":"Brief Bioinform"},{"key":"672_CR44","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/nature08959","volume":"465","author":"D Sprinzak","year":"2010","unstructured":"Sprinzak D, Lakhanpal A, LeBon L, Santat L, Fontes ME, Anderson GA, et al. Cis-interactions between Notch and Delta generate mutually exclusive signaling states. Nature. 2010;465:86\u201390.","journal-title":"Nature"},{"key":"672_CR45","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1145\/272991.272995","volume":"8","author":"M Matsumoto","year":"1998","unstructured":"Matsumoto M, Nishimura T. Mersenne twister: a 623-dimensionally equidistributed uniform pseudorandom number generator. ACM Trans Model Comp Simul. 1998;8:3\u201330.","journal-title":"ACM Trans Model Comp Simul"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12918-018-0672-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12918-018-0672-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12918-018-0672-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T22:18:55Z","timestamp":1694557135000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/s12918-018-0672-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,14]]},"references-count":45,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["672"],"URL":"https:\/\/doi.org\/10.1186\/s12918-018-0672-9","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,14]]},"assertion":[{"value":"5 January 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 December 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Publisher\u2019s Note"}}],"article-number":"7"}}