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

Endocrine Abstracts (2012) 28 S1.1

Genetic models of pituitary disease in multiple endocrine neoplasia type 1 (MEN1)

Rajesh Thakker

Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease characterised by the combined occurrence of parathyroid, pancreatic islet and anterior pituitary tumours. Over 60% of the anterior pituitary tumours in MEN1 patients are prolactinomas, ~25% are somatotrophinomas, ~5% are corticotrophinomas, and the remainder appear to be non-functioning. The MEN1 gene, a tumour suppressor, is located on chromosome 11q13, and more than 1300 MEN1 mutations, which are likely loss-of-function, have been reported. MEN1 encodes a ubiquitously expressed 610-amino acid protein, menin, which has been shown by in vitro studies to have roles in transcriptional regulation, genome stability, cell division, and cell cycle control. To elucidate further the in vivo role of menin, mouse models using conventional or conditional knockout strategies, have been generated through homologous recombination of the mouse Men1 gene. Four conventional Men1 knock-out models have been reported, in which heterozygous (Men1+/−) mice develop multiple tumours of the pancreas, anterior pituitary, and parathyroids. The majority of the pituitary tumours were lacto-somatotrophinomas that also expressed the somatostatin receptor type 2 (SSTR2) and vascular endothelial growth factor-A (VEGF-A). Conditional (i.e. tissue specific) knockout mice have also been generated and these have an advantage in that they do require a sporadic (random) second mutation of the Men1 gene for tumourigenesis, but instead the Men1 alleles can be deleted in all animals at the same time, thereby generating a homogenous population to study. Thus, pancreatic beta-cell-specific Men1−/− mouse models have been generated, utilising the Cre-recombinase under the control of the rat insulin promoter (Rip-Cre), and reported to develop insulinomas. A subset of these conditional knockout mice also developed prolactinomas as Rip-Cre is expressed in the pituitary. Studies of these knockout mice, which represent pre-clinical models, have provided useful insights into the molecular mechanisms that lead to pituitary tumourigenesis.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: MRC Programme Grant - G9825289 and G1000467.

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