Abstract
Gain-of-function mutations in the gene encoding the receptor tyrosine kinase RET have been identified as the aetiological factor for multiple endocrine neoplasia type 2A (MEN2A). MEN2A is a dominantly-inherited cancer predisposition syndrome characterized by medullary thyroid carcinoma, a tumour of the calcitonin-producing thyroid C-cells. There are three isoforms of RET: RET9, RET43 and RET51, and although in vitro evidence suggests they vary in cellular transformation activities, little is known about their function in tumorigenesis in vivo. To address this, we used RET51 cDNA to construct mice in which the most frequent MEN2A mutation, Cys-634-Arg, was expressed under the control of the human calcitonin promoter (CT-2A mice). These mice developed C-cell tumours resembling human MTC and follicular tumours resembling human papillary thyroid carcinoma (PTC) depending on the founder line examined. One founder line developed compound MTC/PTC at low frequency (8%) and pancreatic cystadenocarcinoma. CT-2A mice also displayed a developmental defect in thyroid follicular structure, in which much of the thyroid was occupied by large irregular cystic follicles thought to be derived from the ultimobranchial body, a developmental precursor of the thyroid gland. The CT-2A mice will provide a suitable model to further study the effects of the MEN 2A RET mutation in vivo.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Acton DS, Velthuyzen D, Lips CJ, Hoppener JW . 2000 Oncogene 19: 3121–3125
Airaksinen MS, Titievsky A, Saarma M . 1999 Mol. Cell. Neurosc. 13: 313–325
Asai N, Iwashiti T, Matsuyama M, Takahashi M . 1995 Mol. Cell. Biol. 15: 1613–1619
Baloh RH, Enomoto H, Johnson EMJ, Milbrandt J . 2000 Curr. Op. Neurobiol. 10: 103–110
Bongarzone I, Monzini N, Borrello MG, Carcano C, Ferraresi G, Arighi E, Mondellini P, Della Porta G, Pierotti MA . 1993 Mol. Cell. Biol. 13: 358–366
Borrello MG, Smith DP, Pasini B, Bongarzone I, Greco A, Lorenzo MJ, Arighi E, Miranda C, Eng C, Alberti L, Bocciardi R, Mondellini R, Scopsi L, Romeo G, Ponder BAJP, Pierotti MA . 1995 Oncogene 11: 2419–2427
Bunone G, Uggeri M, Mondellini P, Pierotti MA, Bongarzone I . 2000 Cancer Res. 60: 2845–2849
Caillou B . 1991 Medullary Thyroid Carcinoma Vol. 211: Colloque INSERM. Calmettes C and Guliana JM. (eds) John Libbey Eurotext Ltd.: Paris pp. 53–57
Decker RA . 1993 Surgery 114: 1059–1063
Durbec P, Marcos-Gutierrez CV, Kilkenny C, Grigoriou M, Wartiowaara K, Suvanto P, Smith D, Ponder B, Costantini F, Saarma M, Sariola H, Pachnis V . 1996 Nature 381: 789–993
Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, Holder S, Nihoul-Fekete C, Ponder BAJ, Munnich A . 1994 Nature 367: 378–380
Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjold M, Komminoth P, Hendy GN, Gharib H, Thibodeau SN, Lacroix A, Frilling A, Ponder BAJ, Mulligan LM . 1996 JAMA 276: 1575–1579
Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, Gardner E, Scheumann GF, Jackson CE, Tunnacliffe A, Ponder BAJP . 1994 Hum. Mol. Genet. 3: 237–241
Fabbro D, Di Loreto C, Beltrami CA, Belfiore A, Di Lauro R, Damante G . 1994 Cancer Res. 54: 4744–4749
Farndon JR, Leight GS, Dilley WG, Baylin SB, Smallridge RC, Harrison TS, Wells SAJ . 1986 Br. J. Surg. 73: 278–281
Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, Della Porta G, Fusco A, Vecchio G . 1990 Cell 60: 557–563
Harach HR, Williams ED . 1994 Diseases of the Thyroid. Wheeler, M. H. & Lazarus, J. H. (eds) Chapman and Hall: London pp. 341–363
Hofstra RMW, Landsvater RM, Ceccherini I, Stulp RP, Stewagen T, Luo Y, Pasini B, Hopener JMW, van Ploos A, Romero G . 1994 Nature 367: 275–276
Jhiang SM, Fithian L, Weghorst CM, Clark OH, Falko JM, O'Dorisio TM, Mazzaferri EL . 1996 Thyroid 6: 115–121
Kovacs CS, Mase RM, Kovacs K, Nguyen GK, Chik CL . 1994 Cancer 74: 928–932
Johnston D, Hatzis D, Sunday ME . 1998 Oncogene 16: 167–177
Lazzaro D, Price M, de Felice M, Di Lauro R . 1991 Development 113: 1093–1104
Le Douarin N, Le Lievre C . 1970 Comptes Rendus Hebdomadaires Des Seances de L Academie Des Sciences. D: Sciences Naturelles 270: 2857–2860
Ljungberg O, Ericcson UB, Bodeson L, Thorell J . 1983 Cancer 52: 1053–1061
Lorenzo MJ, Gish GD, Houghton C, Stonehouse TJ, Pawson T, Ponder BA, Smith DP . 1997 Oncogene 14: 763–771
Manley NR, Capecchi MR . 1995 Development 121: 1989–2003
Manley NR, Capecchi MR . 1998 Dev. Biol. 195: 1–15
Marshall GM, Peaston AE, Hocker JE, Smith SA, Hansford LM, Tobias V, Norris MD, Haber M, Smith DP, Lorenzo MJ, Ponder BA, Hancock JF . 1997 Cancer Res. 57: 5399–5405
Michiels FM, Chappuis S, Caillou B, Pasini A, Talbot M, Monier R, Lenoir GM, Feunteun J, Billaud M . 1997 Proc. Nat. Acad. Sci. USA 94: 3330–3335
Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BAJP . 1993 Nature 363: 458–460
Myers SM, Eng C, Ponder BAJ, Mulligan LM . 1995 Oncogene 11: 2039–2045
Oishi S, Sato T, Takiguchi-Shirahama S, Nakamura Y . 1995 Endocrine J. 42: 527–536
Okada Y, Takeyama H, Sato M, Morikawa M, Sobue K, Asai K, Tada T, Kato T, Manabe T . 1999 Int. J. Can. 81: 67–73
Orlandi F, Chiefari E, Caraci P, Mussa A, Gonzatto I, De Giuli P, Giuffrida D, Angeli A, Filetti S . 2001 J Endocrinol. Invest. 24: 51–59
Pachnis V, Mankoo B, Costantini F . 1993 Development 119: 1005–1017
Peleg S, Cote GJ, Abruzzese RV, Gagel RF . 1989 Henry Ford Hosp. Med. J. 37: 194–197
Ponder BA, Smith D . 1996 Adv. Can. Res. 70: 179–222
Portella G, Salvatore D, Botti G, Cerrato A, Zhang L, Mineo A, Chiappetta G, Santelli G, Pozzi L, Vecchio G, Fusco A, Santoro M . 1996 Oncogene 13: 2021–2026
Powell DJJ, Russell J, Nibu K, Li G, Rhee E, Liao M, Goldstein M, Keane WM, Santoro M, Fusco A, Rothstein JL . 1998 Cancer Res. 58: 5523–5528
Romero G, Ronchesto P, Luo Y, Barone V, Seri M, Ceccherini I, Pasini B, Bocchiardi R, Lerone M, Kaariainen H, Martuciello G . 1994 Nature 367: 377–378
Rossel M, Pasini A, Chappuis S, Geneste O, Fournier L, Schuffenecker I, Takahashi M, van Grunsven LA, Urdiales JL, Rudkin BB, Lenoir GM, Billaud M . 1997 Oncogene 14: 265–275
Rossel M, Schuffenecker I, Schlumberger M, Bonnardel C, Modigliani E, Gardet P, Navarro J, Lou Y, Romeo G, Lenoir G, Billaud M . 1995 Hum. Genetics 95: 403–406
Saad MF, Ordonez NG, Rashid RK, Guido JJ, Hill CSJ, Hickey RC, Samaan NA . 1984 Medicine 63: 319–342
Sanchez MP, Silos-Santiago I, Frisen J, He B, Lira SA, Barbacid M . 1996 Nature 382: 70–73
Santoro M, Carlomagno F, Melillo RM, Billaud M, Vecchio G, Fusco A . 1999 J. Endocrin. Invest. 22: 811–819
Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus MH, Difiore PP . 1995 Science 267: 381–383
Santoro M, Chiappetta G, Cerrato A, Salvatore D, Zhang L, Manzo G, Picone A, Portella G, Santelli G, Vecchio G, Fusco A . 1996 Oncogene 12: 1821–1826
Santoro M, Dathan NA, Berlingieri MT, Bongarzone I, Paulin C, Grieco M, Pierotti MA, Vecchio G, Fusco A . 1994 Oncogene 9: 509–516
Schimke RN . 1984 Ann. Rev. Med. 35: 25–31
Schuchardt A, D'Agati V, Larsson Blomberg L, Costantini F, Pachnis V . 1994 Nature 367: 380–383
Segouffin-Cariou C, Billaud M . 2000 J. Biol. Chem. 275: 3568–3576
Shi SR, Key ME, Kalra KL . 1991 J. Histochem. Cytochem. 39: 741–748
Songyang Z, Carraway KL, Eck MJ, Harrison SC, Feldman RA, Mohammed M, Schlessinger J, Hubbard SR, Smith DP, Eng C, Lorenzo MJ, Ponder BAJ, Mayer BJ, Cantley LC . 1995 Nature 373: 536–539
Trupp M, Arenas E, Fainzilber M, Nilsson AS, Sieber BA, Grigoriou M, Kilkenny C, Salazar-Grueso E, Pachnis V, Arumae U . 1996 Nature 381: 785–789
Wetzel BK, Wollman SH . 1969 Endocrinology 84: 563–578
Wollman SH, Hilfer SR . 1978 Anatomical Record 191: 111–121
Acknowledgements
We wish to thank Sara Peleg for kindly supplying the human calcitonin promoter DNA and Massimo Santoro for the anti-TTF-1 antibody. This work was supported by The Cancer Research Campaign (CRC).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Reynolds, L., Jones, K., Winton, D. et al. C-cell and thyroid epithelial tumours and altered follicular development in transgenic mice expressing the long isoform of MEN 2A RET. Oncogene 20, 3986–3994 (2001). https://doi.org/10.1038/sj.onc.1204434
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204434
Keywords
This article is cited by
-
Follicular cell lineage in persistent ultimobranchial remnants of mammals
Cell and Tissue Research (2019)
-
Rodent models of pheochromocytoma, parallels in rodent and human tumorigenesis
Cell and Tissue Research (2018)
-
Consensus on management of advanced medullary thyroid carcinoma on behalf of the Working Group of Thyroid Cancer of the Spanish Society of Endocrinology (SEEN) and the Spanish Task Force Group for Orphan and Infrequent Tumors (GETHI)
Clinical and Translational Oncology (2016)
-
Sprouty1 is a candidate tumor-suppressor gene in medullary thyroid carcinoma
Oncogene (2012)
-
Evaluation of systemic targeting of RET oncogene-based MTC with tumor-selective peptide-tagged Ad vectors in clinical mouse models
Gene Therapy (2011)