A MEN1 pancreatic neuroendocrine tumour mouse model under temporal control.
Lines KE., Vas Nunes RP., Frost M., Yates CJ., Stevenson M., Thakker RV.
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by occurrence of parathyroid tumours and neuroendocrine tumours (NETs) of the pancreatic islets and anterior pituitary. The MEN1 gene, encoding menin, is a tumour suppressor, but its precise role in initiating in vivo tumourigenesis remains to be elucidated. The availability of a temporally controlled conditional MEN1 mouse model would greatly facilitate the study of such early tumourigenic events, and overcome the limitations of other MEN1 knockout models, in which menin is lost from conception or tumour development occurs asynchronously. To generate a temporally controlled conditional mouse model, we crossbred mice with the MEN1 gene floxed by LoxP sites (Men1 L/L ), and mice expressing tamoxifen-inducible Cre recombinase under the control of the rat insulin promoter (RIP2-CreER), to establish a pancreatic β-cell-specific NET model under temporal control (Men1 L/L /RIP2-CreER). Men1 L/L /RIP2-CreER mice aged ~3 months were given tamoxifen in the diet for 5 days, and pancreata harvested 2-2.5, 2.9-3.5 and 4.5-5.5 months later. Control mice did not express Cre and did not receive tamoxifen. Immunostaining of pancreata from tamoxifen-treated Men1 L/L /RIP2-CreER mice, compared to control mice, showed at all ages: loss of menin in all islets; increased islet area (>4.2-fold); increased proliferation of insulin immunostaining β-cells (>2.3-fold) and decreased proliferation of glucagon immunostaining α-cells (>1.7-fold). There were no gender and apoptotic or proliferation differences, and extra-pancreatic tumours were not detected. Thus, we have established a mouse model (Men1 L/L /RIP2-CreER) to study early events in the development of pancreatic β-cell NETs.