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Endocrine Abstracts (2016) 44 OC1.6 | DOI: 10.1530/endoabs.44.OC1.6

SFEBES2016 Oral Communications Early Career Oral Communications (6 abstracts)

A time controlled β-cell specific mouse model Men1L/L/RIP2-CreER for pancreatic neuroendocrine tumours (NETs)

Roeland P Vas Nunes , Morten Frost , Mark Stevenson , Kate E Lines & Rajesh V Thakker

Academic Endocrine Unit, OCDEM, University of Oxford, Oxford, UK.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by occurrence of parathyroid tumours and neuroendocrine tumours (NETs) of the pancreas and pituitary, which is caused by mutations of the MEN1 gene, encoding menin. Mouse models are important in elucidating mechanisms of MEN1 tumourigenesis and treatments, but the current models have limitations. Thus, in conventional heterozygous MEN1 knockout models, tumour development is unpredictable as spontaneous loss of heterozygosity in tumours may arise in different tissues at different times. Conditional models with homozygous Men1 knockout restricted to specific tissue types, using a Cre-LoxP system and a targeted promoter (e.g. UBC9-whole pancreas or RIP2-pancreatic β-cells), overcome this unpredictability, but are of limited use in elucidating early tumourigenic events as in MEN1 one allele is lost from conception. To study early events, conditional models with gene expression under temporal control can be generated by fusing an oestrogen receptor to Cre constructs, to selectively delete both Men1 alleles, by tamoxifen administration, as shown by the development of islet hyperplasia and increased β-cell proliferation in Men1L/L/UBC9-ERt-Cre mice within 1 month after tamoxifen administration. We therefore used Men1L/L/RIP2-CreER mice to establish a pancreatic β-cell-specific NET model under temporal control. Men1L/L/RIP2-CreER mice (12 males and 14 females) aged 12–14 weeks were given tamoxifen in the diet for 5 days, and pancreata harvested 8–10, 12–14, and 25–29 weeks later. Control mice (7 males and 10 females) did not express Cre and did not receive tamoxifen. Immunostaining of pancreata from Men1L/L/RIP2-CreER mice 8–10 weeks after tamoxifen administration showed: loss of menin in all islets; increased islet area (>4.2-fold, P<0.05); and increased β-cell proliferation (>2.5-fold, P<0.013). There were no gender and α-cell proliferation differences. Thus, Men1L/L/RIP2-CreER mice develop insulin-expressing NETs and provide a model to study early events in development of pancreatic β-cell NETs.

Volume 44

Society for Endocrinology BES 2016

Brighton, UK
07 Nov 2016 - 09 Nov 2016

Society for Endocrinology 

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