Introduction: Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) predispose humans to pituitary adenomas, mostly GH and sometimes prolactin-secreting adenomas. Rodent models of heterozygous AIP loss provided mixed results, with little phenotype in heterozygote global knockouts to 80% in somatotroph-specific homozygote knockout animals. However, human patients with an AIP mutation often have mixed GH-PRL adenomas and, in a smaller proportion, pure prolactinomas. Therefore, we have generated a transgenic model with pituitary-specific AIP knockout using an early transcription factor Hesx1.
Aim: To characterize a transgenic mouse model of early stage pituitary-specific deletion of AIP.
Methods: AIP was specifically inactivated in the anterior pituitary at the embryonic stage by crossing animals bearing floxed AIP alleles with mice expressing Cre recombinase under the Hesx1 regulatory element. Tissue was collected for immunohistochemistry and size measurements. IGF1 blood levels were measured at regular intervals.
Results: AIP null mice are significantly larger compared to their littermate controls by the age of 3 months (23.9±2.27 vs 28.5±3.03 g, P<0.01) with higher levels of IGF1 as early as 2 months (333.31±35.70 vs 472.66±86.81 ng/ml, P<0.005). At 15 months, homozygote knockout mice had hypertrophic hearts (9.19±0.43 vs 10.79±1.02 mm, P<0.0001) and the pituitary is enlarged (1097556±220927 vs 2155418±513251 μm2, P=0.02) exhibiting features of hyperplasia and areas of adenomas positive for GH and prolactin. These abnormalities were observed with 100% penetrance. Heterozygote mice overall are not significantly larger, although some animals have abnormal pituitaries, suggesting that penetrance, similar to humans, is incomplete.
Conclusions: Using a transgenic approach we have established a KO mouse model of early AIP deletion specifically in the pituitary. Complete loss of AIP results in increased body size and higher circulating IGF1 levels early on eventually leading to hyperplasia and tumour formation. This model provides an invaluable tool to study AIP-related tumorigenic processes and possible therapeutic interventions.