ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2007) 13 OC22

Mice deleted for a Multiple Endocrine Neoplasia Type 1 (MEN1) allele develop pancreatic, pituitary and parathyroid tumours in association with hypercalcaemia

Manuel Lemos1, Brian Harding1, Michael Bowl1, Anita Reed1, Hilda Tateossian2, Tertius Hough2, William Fraser3, Michael Cheeseman2 & Rajesh Thakker1

1University of Oxford, Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford, United Kingdom; 2Mary Lyon Centre, Medical Research Council, Harwell, United Kingdom; 3Department of Clinical Chemistry, Royal Liverpool University Hospital, Liverpool, United Kingdom.

Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of tumours of the parathyroids, pancreas and pituitary. The MEN1 gene, which is located on chromosome 11q13 and encodes a 610 amino acid protein (menin), belongs to the class of tumour suppressors. To investigate the role of menin in tumour suppression, three different mouse models have been generated through targeted disruption of the Men1 gene. These developed parathyroid, pancreatic and pituitary tumours, but not hypercalcaemia which is a cardinal feature of primary hyperparathyroidism. We have therefore developed another mouse model, by replacing exons 1 and 2 with a neomycin resistance construct that resulted in a loss of the initiation codon, and investigated this for MEN1–associated tumours. Mice were kept in accordance with UK Home Office welfare guidelines and project license restrictions. Heterozygous (+/−) knockout mice were viable and fertile, and 183+/− mice and 70+/+ mice were studied between the ages of 3 and 21 months. Heterozygous (+/−) mice developed parathyroid tumours by age 12 months, pancreatic tumours which were mostly insulinomas by age 9 months, and pituitary tumours which were mostly prolactinomas by age 9 months. Molecular analyses of these tumours revealed loss of heterozygosity consistent with a tumour suppressor role for the Men1 gene. Serum calcium levels were measured at 9-21 months and were higher in heterozygous than in wild-type mice and higher still in those with histological evidence of parathyroid hyperplasia or adenoma (ANOVA with post test for linear trend, P<0.01 at 12 months, P<0.05 at 15 months, P=0.05 at 21 months). Thus, these +/− Men1 knockout mice, which are deleted for exons 1 and 2 and develop hypercalcaemia, are highly representative of MEN1 in man and will help in elucidating further the molecular pathways involved in parathyroid tumourigenesis.

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