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Cortical thymic epithelial cells (cTECs) regulate T cell lineage commitment and positive selection, while medullary (m) TECs impose central tolerance on the T cell repertoire. During thymus organogenesis, these functionally distinct sub-lineages are thought to arise from a common thymic epithelial progenitor cell (TEPC). The mechanisms controlling cTEC and mTEC production from the common TEPC are not however understood. Here, we show that emergence of the earliest mTEC lineage-restricted progenitors requires active NOTCH signaling in progenitor TEC and that, once specified, further mTEC development is NOTCH-independent. In addition, we demonstrate that persistent NOTCH activity favors maintenance of undifferentiated TEPC at the expense of cTEC differentiation. Finally, we uncover a cross-regulatory relationship between NOTCH and FOXN1, a master regulator of TEC differentiation. These data establish NOTCH as a potent regulator of TEPC and mTEC fate during fetal thymus development and are thus of high relevance to strategies aimed at generating\/regenerating functional thymic tissue in vitro and in vivo.<\/jats:p>","DOI":"10.1242\/dev.178582","type":"journal-article","created":{"date-parts":[[2020,5,28]],"date-time":"2020-05-28T09:47:15Z","timestamp":1590659235000},"source":"Crossref","is-referenced-by-count":37,"title":["Canonical Notch signaling controls the early thymic epithelial progenitor cell state and emergence of the medullary epithelial lineage in fetal thymus development"],"prefix":"10.1242","author":[{"given":"Dong","family":"Liu","sequence":"first","affiliation":[{"name":"MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia I.","family":"Kousa","sequence":"additional","affiliation":[{"name":"MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy E.","family":"O'Neill","sequence":"additional","affiliation":[{"name":"MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Rouse","sequence":"additional","affiliation":[{"name":"MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martyna","family":"Popis","sequence":"additional","affiliation":[{"name":"MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison M.","family":"Farley","sequence":"additional","affiliation":[{"name":"MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon R.","family":"Tomlinson","sequence":"additional","affiliation":[{"name":"MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, 5, Little France Drive, Edinburgh EH16 4UU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3124-9178","authenticated-orcid":false,"given":"Svetlana","family":"Ulyanchenko","sequence":"additional","affiliation":[{"name":"Biotech Research and Innovation Centre (BRIC), Ole Maal\u00f8es Vej 5, 2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Guillemot","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5782-6020","authenticated-orcid":false,"given":"Philip A.","family":"Seymour","sequence":"additional","affiliation":[{"name":"NNF Center for Stem Cell Biology, University of Copenhagen, N\u00f8rre Alle 14, DK-2200 Copenhagen N, DK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette C.","family":"J\u00f8rgensen","sequence":"additional","affiliation":[{"name":"NNF Center for Stem Cell Biology, University of Copenhagen, N\u00f8rre Alle 14, DK-2200 Copenhagen N, DK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0858-590X","authenticated-orcid":false,"given":"Palle","family":"Serup","sequence":"additional","affiliation":[{"name":"NNF Center for Stem Cell Biology, University of Copenhagen, N\u00f8rre Alle 14, DK-2200 Copenhagen N, DK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"Koch","sequence":"additional","affiliation":[{"name":"Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL), 1015 Lausanne CH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Freddy","family":"Radtke","sequence":"additional","affiliation":[{"name":"Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL), 1015 Lausanne CH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6326-640X","authenticated-orcid":false,"given":"C. 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