International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


POSTER 220 - THE MEN2A MUTATION IN THE RET ONCOGENE CAUSES MEDULLARY THYROID CARCINOMA IN TRANSGENIC MICE

Dr Aaron Cranston
CRC Department of Oncology
University of Cambridge
Cambridge Institute for Medical Research
Wellcome Trust/MRC Building
Addenbrookes Hospital Site
Hills Road, Cambridge
CB2 2XY
UK

Co-Authors:  Jones K, and Ponder B
Institution:   CRC Department of Oncology, University of Cambridge

The men2a mutation in the ret oncogene causes medullary thyroid carcinoma in transgenic mice

Mutagenesis/transgenics - work completed.

Gain-of-function mutations in RET have been identified in the dominantly-inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2).  MEN2A patients develop MTC: a tumour of the thyroid calcitonin-producing C-cells.  The majority of MEN2A mutations are substitutions of conserved cysteine residues in the extracellular domain of RET that result in disruption of an intramolecular disulphide bond leaving the free cysteine to form an intermolecular bond with an adjacent RET molecule.  Consequently, this leads to ligand-independent dimerisation and inappropriate activation of RET.  To investigate RET function in vivo we generated transgenic lines of mice expressing the MEN2A mutant form of RET in the mouse thyroid gland.  We constructed the transgene such that the most frequent MEN2A mutation, Cys634-->Arg, was expressed under the control of the C-cell specific human calcitonin promoter (CT-RET2A).  Transgenic mice expressing wildtype RET from the calcitonin promoter (CT-RET.WT) served as controls.  The CT-RET2A mice developed C-cell tumours similar to human MTC and follicular tumours similar to papillary thyroid carcinoma; in addition, a developmental defect in thyroid follicular structure was observed.  No phenotype was observed in CT-RET.WT mice up to 2 years of age.  The CT-RET2A mice will provide a suitable model to further study in vivo aspects of inherited MEN2A disease.


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