Somatotroph-specific aryl hydrocarbon receptor interacting protein deficient mice display pre-tumorigenic changes in cell cycle progression and transcriptional control

Abstract

Patients with familial isolated pituitary adenoma are predisposed to pituitary adenomas, which in a subset of cases is due to germline inactivating mutations of the aryl hydrocarbon receptor interacting protein (AIP) gene. Using Cre/lox and Flp/Frt technology, a conditional mouse model was generated to examine the loss of the mouse homolog, Aip, in pituitary somatotrophs. By 40 weeks of age, >80% of somatotroph specific Aip knockout (sAIPKO) mice develop growth hormone (GH) secreting adenomas. The formation of adenomas results in physiologic effects recapitulating the human syndrome of acromegaly, including increased body size, elevated serum growth hormone levels, and glucose intolerance. The pre-tumorigenic Aip-deficient somatotrophs secrete excess GH and exhibit pathologic hyperplasia associated with cytosolic compartmentalization of the cyclin dependent kinase inhibitor p27kip1 and perinuclear accentuation of cyclin dependent kinase-4. The delayed tumor emergence, even with loss of both copies of Aip, implies that additional somatic events are required for adenoma formation. High-throughput mRNA sequencing (RNA-seq) identified genes that were differentially expressed among the control and hyperplastic pituitary tissues related to epigenetics and RNA processing, revealing potential mechanisms involved in the pre-tumorigenic state that ultimately contribute to transformation