{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:19:32Z","timestamp":1790705972655,"version":"4.1.0"},"reference-count":52,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2018,1,1]],"date-time":"2018-01-01T00:00:00Z","timestamp":1514764800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK103785"],"award-info":[{"award-number":["R01DK103785"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005909","name":"Nemzeti Fejleszt\u00e9si Miniszt\u00e9rium","doi-asserted-by":"publisher","award":["124740"],"award-info":[{"award-number":["124740"]}],"id":[{"id":"10.13039\/501100005909","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>The enteric nervous system arises from neural crest cells that migrate, proliferate, and differentiate into enteric neurons and glia within the intestinal wall. Many extracellular matrix (ECM) components are present in the embryonic gut, but their role in regulating ENS development is largely unknown. Here, we identify heparan sulfate proteoglycan proteins, including collagen 18 (Col18) and agrin, as important regulators of enteric neural crest-derived cell (ENCDC) development. In developing avian hindgut, Col18 is expressed at the ENCDC wavefront, while agrin expression occurs later. Both proteins are normally present around enteric ganglia, but are absent in aganglionic gut. Using chick-mouse intestinal chimeras and enteric neurospheres, we show that vagal- and sacral-derived ENCDCs from both species secrete Col18 and agrin. While glia express Col18 and agrin, enteric neurons only express the latter. Functional studies demonstrate that Col18 is permissive while agrin is strongly inhibitory to ENCDC migration, consistent with the timing of their expression during ENS development. We conclude that ENCDCs govern their own migration by actively remodeling their microenvironment through secretion of ECM proteins.<\/jats:p>","DOI":"10.1242\/dev.160317","type":"journal-article","created":{"date-parts":[[2018,4,20]],"date-time":"2018-04-20T05:25:16Z","timestamp":1524201916000},"source":"Crossref","is-referenced-by-count":49,"title":["Collagen 18 and agrin are secreted by enteric neural crest cells to remodel their microenvironment and regulate their migration during ENS development"],"prefix":"10.1242","author":[{"given":"Nandor","family":"Nagy","sequence":"first","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Csilla","family":"Barad","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Hotta","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukhada","family":"Bhave","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Arciero","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Dora","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-847X","authenticated-orcid":false,"given":"Allan M.","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2018,1,1]]},"reference":[{"key":"2021042609265560700_DEV160317C1","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1083\/jcb.152.6.1219","article-title":"The NC1\/endostatin domain of Caenorhabditis elegans type XVIII collagen affects cell migration and axon guidance","volume":"152","author":"Ackley","year":"2001","journal-title":"J. Cell Biol."},{"key":"2021042609265560700_DEV160317C2","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1016\/j.ydbio.2013.08.006","article-title":"Enteric neural crest-derived cells promote their migration by modifying their microenvironment through tenascin-C production","volume":"382","author":"Akbareian","year":"2013","journal-title":"Dev. Biol."},{"key":"2021042609265560700_DEV160317C3","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1387\/ijdb.082667ra","article-title":"Matrix metalloproteinase-2 is involved in the migration and network formation of enteric neural crest-derived cells","volume":"54","author":"Anderson","year":"2010","journal-title":"Int. J. Dev. Biol."},{"key":"2021042609265560700_DEV160317C4","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.mod.2017.04.004","article-title":"Comparative analysis of gene expression profiles for several migrating cell types identifies cell migration regulators","volume":"148","author":"Bae","year":"2017","journal-title":"Mech. Dev."},{"key":"2021042609265560700_DEV160317C5","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1007\/s004410050871","article-title":"Laminin immunoreactivity in enteric ganglia of the chick embryo","volume":"289","author":"Balaskas","year":"1997","journal-title":"Cell Tissue Res."},{"key":"2021042609265560700_DEV160317C6","doi-asserted-by":"publisher","first-page":"e54609","DOI":"10.1371\/journal.pone.0054609","article-title":"A novel role for Lh3 dependent ECM modifications during neural crest cell migration in zebrafish","volume":"8","author":"Banerjee","year":"2013","journal-title":"PLoS ONE"},{"key":"2021042609265560700_DEV160317C7","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1007\/BF01625191","article-title":"Light microscopic immunolocalization of laminin, type IV collagen, nidogen, heparan sulphate proteoglycan and fibronectin in the enteric nervous system of rat and guinea pig","volume":"15","author":"Bannerman","year":"1986","journal-title":"J. Neurocytol."},{"key":"2021042609265560700_DEV160317C8","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1002\/(SICI)1097-0177(199701)208:1&lt;62::AID-AJA6&gt;3.0.CO;2-#","article-title":"Agrin accumulates in the brain microvascular basal lamina during development of the blood-brain barrier","volume":"208","author":"Barber","year":"1997","journal-title":"Dev. Dyn."},{"key":"2021042609265560700_DEV160317C9","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1242\/dev.02346","article-title":"Lack of beta1 integrins in enteric neural crest cells leads to a Hirschsprung-like phenotype","volume":"133","author":"Breau","year":"2006","journal-title":"Development"},{"key":"2021042609265560700_DEV160317C10","doi-asserted-by":"publisher","first-page":"2791","DOI":"10.1242\/dev.031419","article-title":"Beta1 integrins are required for the invasion of the caecum and proximal hindgut by enteric neural crest cells","volume":"136","author":"Breau","year":"2009","journal-title":"Development"},{"key":"2021042609265560700_DEV160317C11","doi-asserted-by":"publisher","first-page":"6184","DOI":"10.1038\/ncomms7184","article-title":"An oncogenic role of Agrin in regulating focal adhesion integrity in hepatocellular carcinoma","volume":"6","author":"Chakraborty","year":"2015","journal-title":"Nat. Commun."},{"key":"2021042609265560700_DEV160317C12","doi-asserted-by":"publisher","first-page":"20927","DOI":"10.1038\/srep20927","article-title":"How tissue mechanical properties affect enteric neural crest cell migration","volume":"6","author":"Chevalier","year":"2016","journal-title":"Sci. Rep."},{"key":"2021042609265560700_DEV160317C13","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1080\/08977190310001621005","article-title":"Structural determinants of heparan sulphate modulation of GDNF signalling","volume":"21","author":"Davies","year":"2003","journal-title":"Growth Factors"},{"key":"2021042609265560700_DEV160317C14","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1093\/emboj\/21.7.1535","article-title":"Lack of collagen XVIII\/endostatin results in eye abnormalities","volume":"21","author":"Fukai","year":"2002","journal-title":"EMBO J."},{"key":"2021042609265560700_DEV160317C15","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1038\/nrgastro.2012.32","article-title":"The enteric nervous system and neurogastroenterology","volume":"9","author":"Furness","year":"2012","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"2021042609265560700_DEV160317C16","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/0306-4522(81)90135-4","article-title":"Ultrastructure of the nerve plexuses of the mammalian intestine: the enteric glial cells","volume":"6","author":"Gabella","year":"1981","journal-title":"Neuroscience"},{"key":"2021042609265560700_DEV160317C17","doi-asserted-by":"publisher","first-page":"37877","DOI":"10.1038\/srep37877","article-title":"Endothelin-3 stimulates cell adhesion and cooperates with beta1-integrins during enteric nervous system ontogenesis","volume":"6","author":"Gazquez","year":"2016","journal-title":"Sci. Rep."},{"key":"2021042609265560700_DEV160317C18","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.ydbio.2016.03.032","article-title":"Clinical aspects of neurointestinal disease: pathophysiology, diagnosis, and treatment","volume":"417","author":"Goldstein","year":"2016","journal-title":"Dev. Biol."},{"key":"2021042609265560700_DEV160317C19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/(SICI)1096-9861(19970623)383:1&lt;1::AID-CNE1&gt;3.0.CO;2-5","article-title":"Distribution and substrate properties of agrin, a heparan sulfate proteoglycan of developing axonal pathways","volume":"383","author":"Halfter","year":"1997","journal-title":"J. Comp. Neurol."},{"key":"2021042609265560700_DEV160317C20","doi-asserted-by":"publisher","first-page":"25404","DOI":"10.1074\/jbc.273.39.25404","article-title":"Collagen XVIII is a basement membrane heparan sulfate proteoglycan","volume":"273","author":"Halfter","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2021042609265560700_DEV160317C21","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1002\/aja.1001950404","article-title":"A series of normal stages in the development of the chick embryo. 1951","volume":"195","author":"Hamburger","year":"1992","journal-title":"Dev. Dyn."},{"key":"2021042609265560700_DEV160317C22","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.matbio.2016.10.002","article-title":"Collagen XVIII in tissue homeostasis and dysregulation-Lessons learned from model organisms and human patients","author":"Heljasvaara","year":"2017","journal-title":"Matrix Biol."},{"key":"2021042609265560700_DEV160317C23","doi-asserted-by":"publisher","first-page":"23486","DOI":"10.1074\/jbc.M312694200","article-title":"Extracellular matrices of the avian ovarian follicle. Molecular characterization of chicken perlecan","volume":"279","author":"Hummel","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021042609265560700_DEV160317C24","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1083\/jcb.152.6.1233","article-title":"Oligomerization-dependent regulation of motility and morphogenesis by the collagen XVIII NC1\/endostatin domain","volume":"152","author":"Kuo","year":"2001","journal-title":"J. Cell Biol."},{"key":"2021042609265560700_DEV160317C25","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1126\/science.aam7511","article-title":"Lineage-dependent spatial and functional organization of the mammalian enteric nervous system","volume":"356","author":"Lasrado","year":"2017","journal-title":"Science"},{"key":"2021042609265560700_DEV160317C26","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1523\/JNEUROSCI.22-03-00876.2002","article-title":"Proteolipid promoter activity distinguishes two populations of NG2-positive cells throughout neonatal cortical development","volume":"22","author":"Mallon","year":"2002","journal-title":"J. Neurosci."},{"key":"2021042609265560700_DEV160317C27","doi-asserted-by":"crossref","first-page":"3909","DOI":"10.1242\/dev.124.19.3909","article-title":"Integrins mediate adhesion to agrin and modulate agrin signaling","volume":"124","author":"Martin","year":"1997","journal-title":"Development"},{"key":"2021042609265560700_DEV160317C28","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1111\/j.1440-169X.2009.01111.x","article-title":"Drosophila multiplexin (Dmp) modulates motor axon pathfinding accuracy","volume":"51","author":"Meyer","year":"2009","journal-title":"Dev. Growth Differ."},{"key":"2021042609265560700_DEV160317C29","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.ydbio.2006.01.032","article-title":"Endothelin-3 regulates neural crest cell proliferation and differentiation in the hindgut enteric nervous system","volume":"293","author":"Nagy","year":"2006","journal-title":"Dev. Biol."},{"key":"2021042609265560700_DEV160317C30","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1007\/s00441-006-0207-3","article-title":"Intestinal coelomic transplants: a novel method for studying enteric nervous system development","volume":"326","author":"Nagy","year":"2006","journal-title":"Cell Tissue Res."},{"key":"2021042609265560700_DEV160317C31","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.semcdb.2017.01.006","article-title":"Enteric nervous system development: a crest cell's journey from neural tube to colon","volume":"66","author":"Nagy","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"2021042609265560700_DEV160317C32","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/dvdy.20933","article-title":"Pelvic plexus contributes ganglion cells to the hindgut enteric nervous system","volume":"236","author":"Nagy","year":"2007","journal-title":"Dev. Dyn."},{"key":"2021042609265560700_DEV160317C33","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.ydbio.2009.03.025","article-title":"Endothelial cells promote migration and proliferation of enteric neural crest cells via beta1 integrin signaling","volume":"330","author":"Nagy","year":"2009","journal-title":"Dev. Biol."},{"key":"2021042609265560700_DEV160317C34","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1002\/dvdy.23767","article-title":"Immunophenotypic characterization of enteric neural crest cells in the developing avian colorectum","volume":"241","author":"Nagy","year":"2012","journal-title":"Dev. Dyn."},{"key":"2021042609265560700_DEV160317C35","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1242\/dev.128132","article-title":"Sonic hedgehog controls enteric nervous system development by patterning the extracellular matrix","volume":"143","author":"Nagy","year":"2016","journal-title":"Development"},{"key":"2021042609265560700_DEV160317C36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/BF00234168","article-title":"Differentiation of sympathetic and enteric neurons of the fowl embryo in grafts to the chorio-allantoic membrane","volume":"208","author":"Newgreen","year":"1980","journal-title":"Cell Tissue Res."},{"key":"2021042609265560700_DEV160317C37","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/0012-1606(88)90217-5","article-title":"Accumulation of components of basal laminae: association with the failure of neural crest cells to colonize the presumptive aganglionic bowel of ls\/ls mutant mice","volume":"125","author":"Payette","year":"1988","journal-title":"Dev. Biol."},{"key":"2021042609265560700_DEV160317C38","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/0012-1606(89)90144-9","article-title":"Molecular mechanisms of avian neural crest cell migration on fibronectin and laminin","volume":"136","author":"Perris","year":"1989","journal-title":"Dev. Biol."},{"key":"2021042609265560700_DEV160317C39","doi-asserted-by":"publisher","first-page":"3456","DOI":"10.1242\/dev.098178","article-title":"Heparan sulfate proteoglycans: a sugar code for vertebrate development?","volume":"142","author":"Poulain","year":"2015","journal-title":"Development"},{"key":"2021042609265560700_DEV160317C40","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1073\/pnas.98.3.1024","article-title":"Interaction of endostatin with integrins implicated in angiogenesis","volume":"98","author":"Rehn","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042609265560700_DEV160317C41","doi-asserted-by":"publisher","first-page":"a004952","DOI":"10.1101\/cshperspect.a004952","article-title":"Heparan sulfate proteoglycans","volume":"3","author":"Sarrazin","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2021042609265560700_DEV160317C42","doi-asserted-by":"publisher","first-page":"4483","DOI":"10.1172\/JCI83178","article-title":"A collagen VI-dependent pathogenic mechanism for Hirschsprung's disease","volume":"125","author":"Soret","year":"2015","journal-title":"J. Clin. Invest."},{"key":"2021042609265560700_DEV160317C43","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.celrep.2012.07.001","article-title":"Target-derived matricryptins organize cerebellar synapse formation through alpha3beta1 integrins","volume":"2","author":"Su","year":"2012","journal-title":"Cell Rep."},{"key":"2021042609265560700_DEV160317C44","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1002\/cne.902910303","article-title":"Distribution of hyaluronic acid and chondroitin sulfate proteoglycans in the presumptive aganglionic terminal bowel of ls\/ls fetal mice: an ultrastructural analysis","volume":"291","author":"Tennyson","year":"1990","journal-title":"J. Comp. Neurol."},{"key":"2021042609265560700_DEV160317C45","doi-asserted-by":"publisher","first-page":"1940","DOI":"10.1016\/j.celrep.2016.01.072","article-title":"Autonomous extracellular matrix remodeling controls a progressive adaptation in muscle stem cell regenerative capacity during development","volume":"14","author":"Tierney","year":"2016","journal-title":"Cell Rep."},{"key":"2021042609265560700_DEV160317C46","doi-asserted-by":"publisher","first-page":"3392","DOI":"10.1074\/jbc.270.7.3392","article-title":"Agrin is a heparan sulfate proteoglycan","volume":"270","author":"Tsen","year":"1995","journal-title":"J. Biol. Chem."},{"key":"2021042609265560700_DEV160317C47","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1007\/BF00228117","article-title":"In vitro assay to test differential substrate affinities of growing axons and migratory cells","volume":"81","author":"Vielmetter","year":"1990","journal-title":"Exp. Brain Res."},{"key":"2021042609265560700_DEV160317C48","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/S0968-0004(00)01731-X","article-title":"The complexities of dystroglycan","volume":"26","author":"Winder","year":"2001","journal-title":"Trends Biochem. Sci."},{"key":"2021042609265560700_DEV160317C49","doi-asserted-by":"publisher","first-page":"e54096","DOI":"10.3791\/54096","article-title":"Stripe assay to study the attractive or repulsive activity of a protein substrate using dissociated hippocampal neurons","volume":"112","author":"Yamagishi","year":"2016","journal-title":"J. Vis. Exp"},{"key":"2021042609265560700_DEV160317C50","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1006\/dbio.2000.0100","article-title":"GDNF is a chemoattractant for enteric neural cells","volume":"229","author":"Young","year":"2001","journal-title":"Dev. Biol."},{"key":"2021042609265560700_DEV160317C51","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/1741-7007-12-23","article-title":"Colonizing while migrating: how do individual enteric neural crest cells behave?","volume":"12","author":"Young","year":"2014","journal-title":"BMC Biol."},{"key":"2021042609265560700_DEV160317C52","doi-asserted-by":"publisher","first-page":"3077","DOI":"10.1007\/s00018-012-1209-9","article-title":"Structural mechanisms of the agrin-LRP4-MuSK signaling pathway in neuromuscular junction differentiation","volume":"70","author":"Zong","year":"2013","journal-title":"Cell. Mol. Life Sci."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dev.160317","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.160317\/1856005\/dev160317.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.160317\/2054772\/dev_160317v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.160317\/2054772\/dev_160317v1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T12:38:03Z","timestamp":1621341483000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/doi\/10.1242\/dev.160317\/264640\/Collagen-18-and-agrin-are-secreted-by-enteric"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,1]]},"references-count":52,"URL":"https:\/\/doi.org\/10.1242\/dev.160317","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2018,1,1]]},"article-number":"dev.160317"}}