{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T10:08:46Z","timestamp":1791022126716,"version":"4.1.0"},"reference-count":20,"publisher":"National Academy of Sciences","issue":"29","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,7,17]]},"abstract":"<jats:p>\n                    p63, a homologue of the tumor suppressor p53, is pivotal for epithelial development, because its loss causes severe epithelial dysgenesis, although no information is so far available on the role of p63 in the thymus. We identified the expression of all p63 isoforms in the developing thymus. The p63\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    thymi show severe abnormalities in size and cellularity, even though the organ expresses normal levels of keratins 5 and 8, indicating a p63-independent differentiation of thymic epithelial cells (TEC). TEC were sufficiently developed to allow a significant degree of education to produce CD4\/CD8 single- and double-positive T cells. To study the selective contribution of transactivation-active p63 (TAp63) and amino-deleted p63 (\u0394Np63) isoforms to the function of the TEC, we genetically complemented p63\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice by crossing p63\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice with transgenic mice expressing either TAp63\u03b1 or \u0394Np63\u03b1 under the control of the keratin 5 promoter. Thymic morphology and cellularity were partially restored by complementation with \u0394Np63, but not TAp63, one downstream effector being fibroblast growth factor receptor 2-IIIb (FgfR2-IIIb). Indeed, FgfR2-IIIb is regulated directly by p63, via its interaction with apobec-1-binding protein-1, and its knockout shows thymic defects similar to those observed in p63\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    thymi. In addition, expression of Jag2, a component of the Notch signaling pathway known to be required for thymic development, was enhanced by p63\n                    <jats:italic>in vivo<\/jats:italic>\n                    genetic complementation. Like Jag2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    thymi, p63\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    thymi also show reduced \u03b3\u03b4 cell formation. Therefore, p63, and particularly the \u0394Np63 isoform, is essential for thymic development via enhanced expression of FgfR2 and Jag2. The action of \u0394Np63 is not due to a direct regulation of TEC differentiation, but it is compatible with maintenance of their \u201cstemness,\u201d the thymic abnormalities resulting from epithelial failure due to loss of stem cells.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0703458104","type":"journal-article","created":{"date-parts":[[2007,7,11]],"date-time":"2007-07-11T21:04:57Z","timestamp":1184187897000},"page":"11999-12004","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":125,"title":["\u0394Np63 regulates thymic development through enhanced expression of FgfR2 and Jag2"],"prefix":"10.1073","volume":"104","author":[{"given":"Eleonora","family":"Candi","sequence":"first","affiliation":[{"name":"*Biochemistry Laboratory, Istituto Dermopatico dell'Immacolata\u2013Istituto di Ricovero e Cura a Carattere Scientifico, Department of Experimental Medicine and Biochemical Sciences, University of Rome \u201cTor Vergata,\u201d 00133 Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Rufini","sequence":"additional","affiliation":[{"name":"*Biochemistry Laboratory, Istituto Dermopatico dell'Immacolata\u2013Istituto di Ricovero e Cura a Carattere Scientifico, Department of Experimental Medicine and Biochemical Sciences, University of Rome \u201cTor Vergata,\u201d 00133 Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Terrinoni","sequence":"additional","affiliation":[{"name":"*Biochemistry Laboratory, Istituto Dermopatico dell'Immacolata\u2013Istituto di Ricovero e Cura a Carattere Scientifico, Department of Experimental Medicine and Biochemical Sciences, University of Rome \u201cTor Vergata,\u201d 00133 Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Giamboi-Miraglia","sequence":"additional","affiliation":[{"name":"*Biochemistry Laboratory, Istituto Dermopatico dell'Immacolata\u2013Istituto di Ricovero e Cura a Carattere Scientifico, Department of Experimental Medicine and Biochemical Sciences, University of Rome \u201cTor Vergata,\u201d 00133 Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Lena","sequence":"additional","affiliation":[{"name":"*Biochemistry Laboratory, Istituto Dermopatico dell'Immacolata\u2013Istituto di Ricovero e Cura a Carattere Scientifico, Department of Experimental Medicine and Biochemical Sciences, University of Rome \u201cTor Vergata,\u201d 00133 Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Mantovani","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences and Biotechnology, University of Milan, 20133 Milan, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Knight","sequence":"additional","affiliation":[{"name":"Toxicology Unit, Medical Research Council, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerry","family":"Melino","sequence":"additional","affiliation":[{"name":"Toxicology Unit, Medical Research Council, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2007,7,17]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80275-0"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/35003607"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/19539"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/19531"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/35043127"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.7.799"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1331"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0952-7915(93)90010-P"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8128249"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1995.tb00096.x"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401926"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.4.1954"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02325"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300746200"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00788"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600708"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.7.1046"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M108080200"},{"key":"e_1_3_4_19_2","first-page":"145","volume":"11","author":"Cheng SH","year":"1991","unstructured":"SH Cheng, JM Penninger, DA Ferrick, TJ Molina, VA Wallace, TW Mak Crit Rev Immunol 11, 145\u2013166 (1991).","journal-title":"Crit Rev Immunol"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.02.045"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0703458104","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T16:52:33Z","timestamp":1649782353000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0703458104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,7,17]]},"references-count":20,"journal-issue":{"issue":"29","published-print":{"date-parts":[[2007,7,17]]}},"alternative-id":["10.1073\/pnas.0703458104"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0703458104","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,7,17]]},"assertion":[{"value":"2007-04-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2007-07-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}