{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T12:30:06Z","timestamp":1790512206400,"version":"4.1.0"},"reference-count":35,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2020,1,1]],"date-time":"2020-01-01T00:00:00Z","timestamp":1577836800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R21 AI107465-A1"],"award-info":[{"award-number":["R21 AI107465-A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000032","name":"Institute of Infection and Immunity","doi-asserted-by":"publisher","award":["FND-154332"],"award-info":[{"award-number":["FND-154332"]}],"id":[{"id":"10.13039\/501100000032","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>The cortical and medullary thymic epithelial cell (cTEC and mTEC) lineages are essential for inducing T cell lineage commitment, T cell positive selection and the establishment of self-tolerance, but the mechanisms controlling their fetal specification and differentiation are poorly understood. Here, we show that Notch signaling is required to specify and expand the mTEC lineage. Notch1 is expressed by and active in TEC progenitors. Deletion of Notch1 in TECs resulted in depletion of mTEC progenitors and dramatic reductions in mTECs during fetal stages, consistent with defects in mTEC specification and progenitor expansion. Conversely, forced Notch signaling in all TEC resulted in widespread expression of mTEC progenitor markers and profound defects in TEC differentiation. In addition, lineage-tracing analysis indicated that all mTECs have a history of receiving a Notch signal, consistent with Notch signaling occurring in mTEC progenitors. These data provide strong evidence for a requirement for Notch signaling in specification of the mTEC lineage.<\/jats:p>","DOI":"10.1242\/dev.178988","type":"journal-article","created":{"date-parts":[[2020,5,28]],"date-time":"2020-05-28T09:43:49Z","timestamp":1590659029000},"source":"Crossref","is-referenced-by-count":29,"title":["NOTCH1 signaling establishes the medullary thymic epithelial cell progenitor pool during mouse fetal development"],"prefix":"10.1242","author":[{"given":"Jie","family":"Li","sequence":"first","affiliation":[{"name":"Department of Genetics, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward L. Y.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto, and Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyun","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luying","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"Z\u00fa\u00f1iga-Pfl\u00fccker","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto, and Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8489-7764","authenticated-orcid":false,"given":"Nancy R.","family":"Manley","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2020,1,1]]},"reference":[{"key":"2021042623460120800_DEV178988C1","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1016\/S1074-7613(02)00321-7","article-title":"Identification and characterization of thymic epithelial progenitor cells","volume":"16","author":"Bennett","year":"2002","journal-title":"Immunity"},{"key":"2021042623460120800_DEV178988C2","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1038\/nature04850","article-title":"Formation of a functional thymus initiated by a postnatal epithelial progenitor cell","volume":"441","author":"Bleul","year":"2006","journal-title":"Nature"},{"key":"2021042623460120800_DEV178988C3","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1038\/s41590-019-0518-7","article-title":"RBPJ-dependent Notch signaling initiates the T cell program in a subset of thymus-seeding progenitors","volume":"20","author":"Chen","year":"2019","journal-title":"Nat. Immunol"},{"key":"2021042623460120800_DEV178988C4","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.ydbio.2016.05.010","article-title":"Temporal and spatial requirements for Hoxa3 in mouse embryonic development","volume":"415","author":"Chojnowski","year":"2016","journal-title":"Dev. Biol."},{"key":"2021042623460120800_DEV178988C5","unstructured":"Cook, A. M.\n           (2010). Proliferation and lineage potential in fetal thymic epithelial progenitor cells. Ph.D. thesis, University of Edinburgh. http:\/\/hdl.handle.net\/1842\/4650"},{"key":"2021042623460120800_DEV178988C6","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1073\/pnas.0711170105","article-title":"Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells","volume":"105","author":"Depreter","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042623460120800_DEV178988C7","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1016\/j.celrep.2016.03.048","article-title":"HDAC3 is a master regulator of mTEC development","volume":"15","author":"Goldfarb","year":"2016","journal-title":"Cell Rep."},{"key":"2021042623460120800_DEV178988C8","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/S0925-4773(01)00333-1","article-title":"Gcm2 and Foxn1 mark early parathyroid- and thymus-specific domains in the developing third pharyngeal pouch","volume":"103","author":"Gordon","year":"2001","journal-title":"Mech. Dev."},{"key":"2021042623460120800_DEV178988C9","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1038\/ni1064","article-title":"Functional evidence for a single endodermal origin for the thymic epithelium","volume":"5","author":"Gordon","year":"2004","journal-title":"Nat. Immunol."},{"key":"2021042623460120800_DEV178988C10","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/1471-213X-7-69","article-title":"Specific expression of lacZ and cre recombinase in fetal thymic epithelial cells by multiplex gene targeting at the Foxn1 locus","volume":"7","author":"Gordon","year":"2007","journal-title":"BMC Dev. Biol."},{"key":"2021042623460120800_DEV178988C11","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.ydbio.2009.12.026","article-title":"Evidence for an early role for BMP4 signaling in thymus and parathyroid morphogenesis","volume":"339","author":"Gordon","year":"2010","journal-title":"Dev. Biol."},{"key":"2021042623460120800_DEV178988C12","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1016\/j.immuni.2009.09.024","article-title":"Spatial mapping of thymic stromal microenvironments reveals unique features influencing T lymphoid differentiation","volume":"31","author":"Griffith","year":"2009","journal-title":"Immunity"},{"key":"2021042623460120800_DEV178988C13","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1038\/ni1438","article-title":"Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin","volume":"8","author":"Hamazaki","year":"2007","journal-title":"Nat. Immunol."},{"key":"2021042623460120800_DEV178988C14","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.4049\/jimmunol.170.3.1299","article-title":"Entry into the thymic microenvironment triggers Notch activation in the earliest migrant T cell progenitors","volume":"170","author":"Harman","year":"2003","journal-title":"J. Immunol."},{"key":"2021042623460120800_DEV178988C15","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1006\/dbio.2000.9732","article-title":"Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures","volume":"222","author":"H\u00e9bert","year":"2000","journal-title":"Dev. Biol."},{"key":"2021042623460120800_DEV178988C16","doi-asserted-by":"publisher","first-page":"2507","DOI":"10.1084\/jem.20080134","article-title":"Delta-like 4 is indispensable in thymic environment specific for T cell development","volume":"205","author":"Hozumi","year":"2008","journal-title":"J. Exp. Med."},{"key":"2021042623460120800_DEV178988C17","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1016\/j.celrep.2014.08.070","article-title":"Global transcriptional profiling reveals distinct functions of thymic stromal subsets and age-related changes during thymic involution","volume":"9","author":"Ki","year":"2014","journal-title":"Cell Rep."},{"key":"2021042623460120800_DEV178988C18","doi-asserted-by":"publisher","first-page":"11822","DOI":"10.1073\/pnas.95.20.11822","article-title":"Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment","volume":"95","author":"Klug","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042623460120800_DEV178988C19","doi-asserted-by":"publisher","first-page":"a011213","DOI":"10.1101\/cshperspect.a011213","article-title":"Notch signaling","volume":"4","author":"Kopan","year":"2012","journal-title":"Cold Spring Harbor Perspect. Biol."},{"key":"2021042623460120800_DEV178988C20","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1242\/dev.119529","article-title":"Second-generation Notch1 activity-trap mouse line (N1IP::CreHI) provides a more comprehensive map of cells experiencing Notch1 activity","volume":"142","author":"Liu","year":"2015","journal-title":"Development"},{"key":"2021042623460120800_DEV178988C21","doi-asserted-by":"publisher","DOI":"10.1242\/dev.178582"},{"key":"2021042623460120800_DEV178988C22","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput Cre reporting and characterization system for the whole mouse brain","volume":"13","author":"Madisen","year":"2010","journal-title":"Nat. Neurosci."},{"key":"2021042623460120800_DEV178988C23","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/S1074-7613(03)00270-X","article-title":"Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells","volume":"19","author":"Maekawa","year":"2003","journal-title":"Immunity"},{"key":"2021042623460120800_DEV178988C24","doi-asserted-by":"publisher","first-page":"1756","DOI":"10.1016\/j.molimm.2009.01.015","article-title":"Notch activation in thymic epithelial cells induces development of thymic microenvironments","volume":"46","author":"Masuda","year":"2009","journal-title":"Mol. Immunol."},{"key":"2021042623460120800_DEV178988C25","doi-asserted-by":"publisher","first-page":"14920","DOI":"10.1073\/pnas.2436557100","article-title":"Notch signaling controls multiple steps of pancreatic differentiation","volume":"100","author":"Murtaugh","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042623460120800_DEV178988C26","doi-asserted-by":"publisher","first-page":"e1002348","DOI":"10.1371\/journal.pgen.1002348","article-title":"Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but is dispensable for medullary sublineage divergence","volume":"7","author":"Nowell","year":"2011","journal-title":"PLoS Genet."},{"key":"2021042623460120800_DEV178988C27","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/1471-213X-13-15","article-title":"A bright single-cell resolution live imaging reporter of Notch signaling in the mouse","volume":"13","author":"Nowotschin","year":"2013","journal-title":"BMC Dev. Biol."},{"key":"2021042623460120800_DEV178988C28","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/S1074-7613(00)80105-3","article-title":"Notch1 expression in early lymphopoiesis influences B versus T lineage determination","volume":"11","author":"Pui","year":"1999","journal-title":"Immunity"},{"key":"2021042623460120800_DEV178988C29","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1002\/eji.201041375","article-title":"Ontogeny of thymic cortical epithelial cells expressing the thymoproteasome subunit \u03b25t","volume":"41","author":"Ripen","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"2021042623460120800_DEV178988C30","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1038\/414763a","article-title":"Thymus medulla consisting of epithelial islets each derived from a single progenitor","volume":"414","author":"Rodewald","year":"2001","journal-title":"Nature"},{"key":"2021042623460120800_DEV178988C31","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1038\/nature04813","article-title":"Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium","volume":"441","author":"Rossi","year":"2006","journal-title":"Nature"},{"key":"2021042623460120800_DEV178988C32","doi-asserted-by":"publisher","first-page":"130","DOI":"10.4049\/jimmunol.182.1.130","article-title":"Checkpoints in the development of thymic cortical epithelial cells","volume":"182","author":"Shakib","year":"2009","journal-title":"J. Immunol."},{"key":"2021042623460120800_DEV178988C33","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1126\/science.1123497","article-title":"Evidence for a functional second thymus in mice","volume":"312","author":"Terszowski","year":"2006","journal-title":"Science"},{"key":"2021042623460120800_DEV178988C34","doi-asserted-by":"publisher","first-page":"2819","DOI":"10.1016\/j.celrep.2016.02.080","article-title":"Identification of a bipotent epithelial progenitor population in the adult thymus","volume":"14","author":"Ulyanchenko","year":"2016","journal-title":"Cell Rep."},{"key":"2021042623460120800_DEV178988C35","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.ydbio.2004.01.014","article-title":"Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway","volume":"269","author":"Yang","year":"2004","journal-title":"Dev. Biol."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dev.178988","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.178988\/1967769\/dev178988.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.178988\/2064967\/dev_178988v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.178988\/2064967\/dev_178988v1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T18:52:56Z","timestamp":1621363976000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/doi\/10.1242\/dev.178988\/266951\/NOTCH1-signaling-establishes-the-medullary-thymic"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,1]]},"references-count":35,"URL":"https:\/\/doi.org\/10.1242\/dev.178988","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/600817","asserted-by":"object"}]},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2020,1,1]]},"article-number":"dev.178988"}}