Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized in man by parathyroid, pancreatic, pituitary and adrenal tumours. The MEN1 gene encodes a 610-amino acid protein (menin) which is a tumour suppressor. To investigate the in vivo role of menin, we developed a mouse model, by deleting Men1 exons 1 and 2 and investigated this for MEN1-associated tumours and serum abnormalities. Men1 +/− mice were viable and fertile, and 220 Men1 +/− and 94 Men1 +/+ mice were studied between the ages of 3 and 21 months. Survival in Men1 +/− mice was significantly lower than in Men1 +/+ mice (<68% vs >85%, P<0.01). Men1 +/− mice developed, by 9 months of age, parathyroid hyperplasia, pancreatic tumours which were mostly insulinomas, by 12 months of age, pituitary tumours which were mostly prolactinomas, and by 15 months parathyroid adenomas and adrenal cortical tumours. Loss of heterozygosity and menin expression was demonstrated in the tumours, consistent with a tumour suppressor role for the Men1 gene. Men1 +/− mice with parathyroid neoplasms were hypercalcaemic and hypophosphataemic, with inappropriately normal serum parathyroid hormone concentrations. Pancreatic and pituitary tumours expressed chromogranin A (CgA), somatostatin receptor type 2 and vascular endothelial growth factor-A. Serum CgA concentrations in Men1 +/− mice were not elevated. Adrenocortical tumours, which immunostained for 3-β-hydroxysteroid dehydrogenase, developed in seven Men1 +/− mice, but resulted in hypercorticosteronaemia in one out of the four mice that were investigated. Thus, these Men1 +/− mice are representative of MEN1 in man, and will help in investigating molecular mechanisms and treatments for endocrine tumours.
Brian Harding, Manuel C Lemos, Anita A C Reed, Gerard V Walls, Jeshmi Jeyabalan, Michael R Bowl, Hilda Tateossian, Nicky Sullivan, Tertius Hough, William D Fraser, Olaf Ansorge, Michael T Cheeseman and Rajesh V Thakker
Iain R Thompson, Annisa N Chand, Peter J King, Olaf Ansorge, Niki Karavitaki, Ceri Alexander Jones, Dolkun Rahmutula, David G Gardner, Vladimir Zivkovic, Caroline P Wheeler-Jones, Imelda M McGonnell, Márta Korbonits, Richard A Anderson, John A H Wass, Alan S McNeilly and Robert C Fowkes
C-type natriuretic peptide (CNP/Nppc) is expressed at high levels in the anterior pituitary of rats and mice and activates guanylyl cyclase B receptors (GC-B/Npr2) to regulate hormone secretion. Mutations in NPR2/Npr2 can cause achondroplasia, GH deficiency, and female infertility, yet the normal expression profile within the anterior pituitary remains to be established in humans. The current study examined the expression profile and transcriptional regulation of NPR2 and GC-B protein in normal human fetal pituitaries, normal adult pituitaries, and human pituitary adenomas using RT-PCR and immunohistochemistry. Transcriptional regulation of human NPR2 promoter constructs was characterized in anterior pituitary cell lines of gonadotroph, somatolactotroph, and corticotroph origin. NPR2 was detected in all human fetal and adult pituitary samples regardless of age or sex, as well as in all adenoma samples examined regardless of tumor origin. GC-B immunoreactivity was variable in normal pituitary, gonadotrophinomas, and somatotrophinomas. Maximal transcriptional regulation of the NPR2 promoter mapped to a region within −214 bp upstream of the start site in all anterior pituitary cell lines examined. Electrophoretic mobility shift assays revealed that this region contains Sp1/Sp3 response elements. These data are the first to show NPR2 expression in normal human fetal and adult pituitaries and adenomatous pituitary tissue and suggest a role for these receptors in both pituitary development and oncogenesis, introducing a new target to manipulate these processes in pituitary adenomas.