C-cell and thyroid epithelial tumours and altered follicular development in transgenic mice expressing the long isoform of MEN 2A RET

Gain-of-function mutations in the gene encoding the receptor tyrosine kinas e RET have been identified as the aetiological factor for multiple endocrin e neoplasia type 2A (MEN2A). MEN2A is a dominantly-inherited cancer predisp osition 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 i n tumorigenesis in vivo. To address this, we used RET51 cDNA to construct m ice in which the most frequent MEN2A mutation, Cys-634-Arg, was expressed u nder the control of the human calcitonin promoter (CT-2A mice), These mice developed C-cell tumours resembling human MTC and follicular tumours resemb ling 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 development al defect in thyroid follicular structure, in which much of the thyroid was occupied by large irregular cystic follicles thought to be derived from th e ultimobranchial body, a developmental precursor of the thyroid gland, The CT-2A mice will provide a suitable model to further study the effects of t he MEN 2A RET mutation in vivo.