{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T20:27:04Z","timestamp":1669235224834},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2017,10,1]],"date-time":"2017-10-01T00:00:00Z","timestamp":1506816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Scientific Research on Innovative Areas"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,12,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Lineage-specific Cre Tg mice are widely used to delineate the functions of genes in a tissue-specific manner. Several T-cell-specific promoter cassettes have been developed; however, the activities of those promoters in non-T cells have not been investigated extensively. Here, we report that CD2-Cre-mediated deletion of Erk proteins by generating CD2-Cre \u00d7 Erk1\u2013\/\u2013Erk2flox\/flox (Erk\u2206CD2-Cre) mice results in abnormal cartilage hyperplasia. Histological analysis revealed that this abnormality is caused by aberrant hyperplasia of chondrocytes. The presence of Erk-deficient T cells is not required for this chondroma formation, as it was similarly observed in the absence of T cells in a CD3\u03b5-deficient background. In addition, adoptive transfer of bone marrow cells from Erk\u2206CD2-Cre mice to wild-type recipients did not cause chondroma formation, suggesting that Erk-deficient non-immune cells are responsible for this abnormality. By tracing Cre-expressed tissues using a ROSA26-STOP-RFP allele, we found that the chondroma emitted RFP fluorescence, indicating that functional Cre is expressed in hyperplastic chondrocytes in Erk\u2206CD2-Cre mice. Furthermore, RFP+ chondrocytes were also found in an Erk-sufficient background, albeit without aberrant growth. These results suggest that unexpected expression of CD2-driven Cre in chondrocytes generates Erk-deficient chondrocytes, resulting in hyperplastic cartilage formation. Recently, two independent reports showed that CD4-Cre-mediated Ras-Erk signaling ablation led to similar abnormal cartilage formation (Guittard, G., Gallardo, D. L., Li, W. et al. 2017. Unexpected cartilage phenotype in CD4-Cre-conditional SOS-deficient mice. Front. Immunol. 8:343; Wehenkel, M., Corr, M., Guy, C. S. et al. 2017. Extracellular signal-regulated kinase signaling in CD4-expressing cells inhibits osteochondromas. Front. Immunol. 8:482). Together with these reports, our study suggests that an unexpected link exists between T-like cell and chondrocyte lineages during ontogeny.<\/jats:p>","DOI":"10.1093\/intimm\/dxx056","type":"journal-article","created":{"date-parts":[[2017,10,27]],"date-time":"2017-10-27T19:11:50Z","timestamp":1509131510000},"page":"479-485","source":"Crossref","is-referenced-by-count":1,"title":["Spontaneous chondroma formation in CD2-Cre-driven Erk-deficient mice"],"prefix":"10.1093","volume":"29","author":[{"given":"Moe","family":"Shiokawa","sequence":"first","affiliation":[{"name":"Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Japan"},{"name":"Department of Molecular Immunology, Research Institute for Microbial Diseases"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiuyuan","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Japan"},{"name":"Department of Molecular Immunology, Research Institute for Microbial Diseases"},{"name":"Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasunobu","family":"Miyake","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eri","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Japan"},{"name":"Department of Molecular Immunology, Research Institute for Microbial Diseases"},{"name":"Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gilles","family":"Pag\u00e8s","sequence":"additional","affiliation":[{"name":"Institute for Research on Cancer & Aging, Nice (IRCAN), CNRS, INSERM, Centre A. Lacassagne, University of Nice-Sophia Antipolis, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacques","family":"Pouyss\u00e9gur","sequence":"additional","affiliation":[{"name":"Institute for Research on Cancer & Aging, Nice (IRCAN), CNRS, INSERM, Centre A. Lacassagne, University of Nice-Sophia Antipolis, France"},{"name":"Medical Biology Department, Centre Scientifique de Monaco (CSM), Monaco"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masato","family":"Ogata","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Proteomics, Graduate School of Medicine, Mie University, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sho","family":"Yamasaki","sequence":"additional","affiliation":[{"name":"Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Japan"},{"name":"Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Japan"},{"name":"Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2017,11,2]]},"reference":[{"key":"2022082522173822600_CIT0001","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1002\/immu.200310005","article-title":"Transgenic mice with hematopoietic and lymphoid specific expression of Cre","volume":"33","author":"de Boer","year":"2003","journal-title":"Eur. J. Immunol"},{"key":"2022082522173822600_CIT0002","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/0092-8674(94)90140-6","article-title":"A lineage-specific transcriptional silencer regulates CD4 gene expression during T lymphocyte development","volume":"77","author":"Sawada","year":"1994","journal-title":"Cell"},{"key":"2022082522173822600_CIT0003","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1093\/intimm\/2.2.173","article-title":"Disruption of thymocyte development and lymphomagenesis induced by SV40 T-antigen","volume":"2","author":"Garvin","year":"1990","journal-title":"Int. Immunol"},{"key":"2022082522173822600_CIT0004","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/ni.2843","article-title":"Quantitative proteomics analysis of signalosome dynamics in primary T cells identifies the surface receptor CD6 as a Lat adaptor-independent TCR signaling hub","volume":"15","author":"Roncagalli","year":"2014","journal-title":"Nat. Immunol"},{"key":"2022082522173822600_CIT0005","doi-asserted-by":"crossref","first-page":"11115","DOI":"10.1073\/pnas.1406259111","article-title":"The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells","volume":"111","author":"Giordano","year":"2014","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022082522173822600_CIT0006","doi-asserted-by":"crossref","first-page":"8319","DOI":"10.1073\/pnas.90.18.8319","article-title":"Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation","volume":"90","author":"Pag\u00e8s","year":"1993","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2022082522173822600_CIT0007","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1080\/02699050500284218","article-title":"The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions","volume":"24","author":"Yoon","year":"2006","journal-title":"Growth Factors"},{"key":"2022082522173822600_CIT0008","doi-asserted-by":"crossref","first-page":"5613","DOI":"10.1074\/jbc.275.8.5613","article-title":"Opposing role of mitogen-activated protein kinase subtypes, erk-1\/2 and p38, in the regulation of chondrogenesis of mesenchymes","volume":"275","author":"Oh","year":"2000","journal-title":"J. Biol. Chem"},{"key":"2022082522173822600_CIT0009","doi-asserted-by":"crossref","first-page":"4588","DOI":"10.1074\/jbc.M309805200","article-title":"The MEK-ERK signaling pathway is a negative regulator of cartilage-specific gene expression in embryonic limb mesenchyme","volume":"279","author":"Bobick","year":"2004","journal-title":"J. Biol. Chem"},{"key":"2022082522173822600_CIT0010","doi-asserted-by":"crossref","first-page":"5843","DOI":"10.1128\/MCB.01549-08","article-title":"Extracellular signal-regulated kinase 1 (ERK1) and ERK2 play essential roles in osteoblast differentiation and in supporting osteoclastogenesis","volume":"29","author":"Matsushita","year":"2009","journal-title":"Mol. Cell. Biol"},{"key":"2022082522173822600_CIT0011","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1101\/gad.1179104","article-title":"Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype","volume":"18","author":"Murakami","year":"2004","journal-title":"Genes Dev"},{"key":"2022082522173822600_CIT0012","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1126\/science.286.5443.1374","article-title":"Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice","volume":"286","author":"Pag\u00e8s","year":"1999","journal-title":"Science"},{"key":"2022082522173822600_CIT0013","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1046\/j.1365-2443.2003.00680.x","article-title":"Essential role for ERK2 mitogen-activated protein kinase in placental development","volume":"8","author":"Hatano","year":"2003","journal-title":"Genes Cells"},{"key":"2022082522173822600_CIT0014","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1002\/eji.200636745","article-title":"Faithful activation of an extra-bright red fluorescent protein in \u201cknock-in\u201d Cre-reporter mice ideally suited for lineage tracing studies","volume":"37","author":"Luche","year":"2007","journal-title":"Eur. J. Immunol"},{"key":"2022082522173822600_CIT0015","doi-asserted-by":"crossref","first-page":"4641","DOI":"10.1002\/j.1460-2075.1995.tb00146.x","article-title":"Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene","volume":"14","author":"Malissen","year":"1995","journal-title":"EMBO J"},{"key":"2022082522173822600_CIT0016","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1002\/jor.21262","article-title":"Genetic inactivation of ERK1 and ERK2 in chondrocytes promotes bone growth and enlarges the spinal canal","volume":"29","author":"Sebastian","year":"2011","journal-title":"J. Orthop. Res"},{"key":"2022082522173822600_CIT0017","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3389\/fimmu.2017.00343","article-title":"Unexpected cartilage phenotype in CD4-Cre-conditional SOS-deficient mice","volume":"8","author":"Guittard","year":"2017","journal-title":"Front. Immunol"},{"key":"2022082522173822600_CIT0018","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3389\/fimmu.2017.00482","article-title":"Extracellular signal-regulated kinase signaling in CD4-expressing cells inhibits osteochondromas","volume":"8","author":"Wehenkel","year":"2017","journal-title":"Front. Immunol"},{"key":"2022082522173822600_CIT0019","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1073\/pnas.1615973114","article-title":"Trogocytosis of peptide-MHC class II complexes from dendritic cells confers antigen-presenting ability on basophils","volume":"114","author":"Miyake","year":"2017","journal-title":"Proc. Natl Acad. Sci. USA"}],"container-title":["International Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/29\/10\/479\/45537743\/intimm_29_10_479.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/29\/10\/479\/45537743\/intimm_29_10_479.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T22:18:06Z","timestamp":1661465886000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/intimm\/article\/29\/10\/479\/4587485"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10]]},"references-count":19,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2017,11,2]]},"published-print":{"date-parts":[[2017,12,18]]}},"URL":"https:\/\/doi.org\/10.1093\/intimm\/dxx056","relation":{},"ISSN":["0953-8178","1460-2377"],"issn-type":[{"value":"0953-8178","type":"print"},{"value":"1460-2377","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,10]]},"published":{"date-parts":[[2017,10]]}}}