{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T15:44:01Z","timestamp":1765295041992,"version":"3.41.2"},"reference-count":21,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T00:00:00Z","timestamp":1552867200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17H03550, 17K19527, 16K08466"],"award-info":[{"award-number":["17H03550, 17K19527, 16K08466"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genesis"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Medullary thyroid carcinoma (MTC) develops from hyperplasia of thyroid C cells and represents one of the major causes of thyroid cancer mortality. Mutations in the cysteine\u2010rich domain (CRD) of the <jats:italic>RET<\/jats:italic> gene are the most prevalent genetic cause of MTC. The current consensus holds that such cysteine mutations cause ligand\u2010independent dimerization and constitutive activation of RET. However, given the number of the CRD mutations left uncharacterized, our understanding of the pathogenetic mechanisms by which CRD mutations lead to MTC remains incomplete. We report here that RET(C618F), a mutation identified in MTC patients, displays moderately high basal activity and requires the ligand for its full activation. To assess the biological significance of <jats:italic>RET(C618F)<\/jats:italic> in organogenesis, we generated a knock\u2010in mouse line conditionally expressing <jats:italic>RET(C618F)<\/jats:italic> cDNA by the <jats:italic>Ret<\/jats:italic> promoter. The <jats:italic>RET(C618F)<\/jats:italic> allele can be made to be Ret\u2010null and express mCherry by Cre\u2010loxP recombination, which allows the assessment of the biological influence of RET(C618F) in vivo. Mice expressing RET(C618F) display mild C cell hyperplasia and increased numbers of enteric neurons, indicating that RET(C618F) confers gain\u2010of\u2010function phenotypes. This mouse line serves as a novel biological platform for investigating pathogenetic mechanisms involved in MTC and enteric hyperganglionosis.<\/jats:p>","DOI":"10.1002\/dvg.23292","type":"journal-article","created":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T04:57:22Z","timestamp":1552971442000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mice conditionally expressing RET(C618F) mutation display C cell hyperplasia and hyperganglionosis of the enteric nervous system"],"prefix":"10.1002","volume":"57","author":[{"given":"Mitsumasa","family":"Okamoto","sequence":"first","affiliation":[{"name":"Division for Neural Differentiation and Regeneration, Department of Physiology and Cell Biology Kobe University Graduate School of Medicine  Kobe Hyogo Japan"},{"name":"Department of Pediatric Surgery Takatsuki General Hospital  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuta","family":"Yoshioka","sequence":"additional","affiliation":[{"name":"Division for Neural Differentiation and Regeneration, Department of Physiology and Cell Biology Kobe University Graduate School of Medicine  Kobe Hyogo Japan"},{"name":"Division of Hepato\u2010Biliary\u2010Pancreatic surgery, Department of Physiology and Cell Biology Kobe University Graduate School of Medicine  Kobe Hyogo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kosaku","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Surgery Hyogo Prefectural Kobe Children's Hospital  Kobe Hyogo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuko","family":"Bito","sequence":"additional","affiliation":[{"name":"Division of Pediatric Surgery, Department of Surgery Kobe University Graduate School of Medicine  Kobe Hyogo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takumi","family":"Fukumoto","sequence":"additional","affiliation":[{"name":"Division of Hepato\u2010Biliary\u2010Pancreatic surgery, Department of Physiology and Cell Biology Kobe University Graduate School of Medicine  Kobe Hyogo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3420-1746","authenticated-orcid":false,"given":"Toshihiro","family":"Uesaka","sequence":"additional","affiliation":[{"name":"Division for Neural Differentiation and Regeneration, Department of Physiology and Cell Biology Kobe University Graduate School of Medicine  Kobe Hyogo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8004-8885","authenticated-orcid":false,"given":"Hideki","family":"Enomoto","sequence":"additional","affiliation":[{"name":"Division for Neural Differentiation and Regeneration, Department of Physiology and Cell Biology Kobe University Graduate School of Medicine  Kobe Hyogo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,3,18]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijsu.2017.02.064"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203648"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.15.3.1613"},{"issue":"3","key":"e_1_2_5_5_1","first-page":"391","article-title":"The different RET\u2010activating capability of mutations of cysteine 620 or cysteine 634 correlates with the multiple endocrine neoplasia type 2 disease phenotype","volume":"57","author":"Carlomagno F.","year":"1997","journal-title":"Cancer Research"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.4.1579"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.050607"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M403726200"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128.20.3963"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.10.032"},{"issue":"14","key":"e_1_2_5_11_1","first-page":"2870","article-title":"Biological properties of ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype","volume":"57","author":"Ito S.","year":"1997","journal-title":"Cancer Research"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1067081"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.7.3330"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/363458a0"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.124.20.4065"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204434"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7824936"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/367380a0"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M203580200"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-199409000-00002"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197308302890901"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22378"}],"container-title":["genesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fdvg.23292","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/dvg.23292","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/dvg.23292","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/am-pdf\/10.1002%2Fdvg.23292","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/dvg.23292","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T09:52:32Z","timestamp":1694339552000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/dvg.23292"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,18]]},"references-count":21,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2019,5]]}},"alternative-id":["10.1002\/dvg.23292"],"URL":"https:\/\/doi.org\/10.1002\/dvg.23292","archive":["Portico"],"relation":{},"ISSN":["1526-954X","1526-968X"],"issn-type":[{"type":"print","value":"1526-954X"},{"type":"electronic","value":"1526-968X"}],"subject":[],"published":{"date-parts":[[2019,3,18]]},"assertion":[{"value":"2019-01-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e23292"}}