SFEBES2019 ORAL COMMUNICATIONS Neuroendocrinology, Pituitary and Neoplasia (6 abstracts)
Investigating the role of AIP in pituitary tumourigenesis
Anisha Mistry 1 , Antonia Solomou 1, , Maria Lillina Vignola 1, , Chung Thong Lim 1 , Maria Herincs 1 , Francisca Caimari 1, , Alejandro Ibáñez Costa 1, , Federica Begalli 1, , Angelica Gualtieri 1 , Federico Roncaroli 6 , Karine Rizzoti 7 , Carles Gaston-Massuet 1 & Márta Korbonits 1
1Queen Mary University, London, UK; 2Kings College London, London, UK; 3University College London, London, UK; 4Maimondes Biomedical Research Institute, Andalusia, Spain; 5Imperial College London, London, UK; 6The University of Manchester, Manchester, UK; 7The Francis Crick Institute, London, UK
Introduction: Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene predispose to growth hormone (GH, 90% of patients) or prolactin (PRL)-secreting tumours, with negligible number of patients with other pituitary tumour types. Animal models of acromegaly are scarce and Aip models have controversial data. Therefore we have generated two pituitary-specific Aip knockout mouse models to study the consequences of loss of AIP protein and understand its role in tumourigenesis.
Models and phenotype: Our AipFlox/Flox;Hesx1Cre/+ model abrogates Aip in cells expressing the early pituitary transcription factor Hesx1, specifically targeting the anterior pituitary cells from E8.5. The inducible AipFlox/Flox;Sox2CreERT2/+ model deletes Aip upon administration of tamoxifen exclusively in Sox2-expressing cells, which form the pituitary stem-cell niche.
Results: The AipFlox/Flox;Hesx1Cre/+ model mirrors the human phenotype, showing an increased body size, enlarged organs (e.g. heart), high circulating IGF-1 and 85% penetrance of functional pituitary tumours at 15 months. Contrastingly, the tamoxifen-inducible Sox2-based model showed no increased body size or altered IGF-1 up to 18 months from injecting at 3 or 8 weeks old. A developmental abnormality localised in the pituitary intermediate lobe (IL) is observed in at least 50% of AipFlox/Flox;Hesx1Cre/+ embryos and tamoxifen-injected AipFlox/Flox;Sox2CreERT2/+ adults. Furthermore, tamoxifen-injection during pregnancy resulted in embryonic IL abnormality, recapitulating the AipFlox/Flox;Hesx1Cre/+ embryonic phenotype. The observed abnormality consists of ectopic PIT-1, GH and PRL-expressing cells in the IL Moreover, some of the tumours in adult animals arise from these altered cells of the IL.
Conclusions: Our data suggest that Aip loss leads to a pituitary development defect with ectopically expressed GH and PRL, ultimately promoting tumourigenesis. This supports the clinical observations, that AIP mutation positive patients invariably develop disease during childhood and there is a lack of somatic AIP mutations in pituitary tumours. Overall, this highlights AIP’s key role in tumours and normal pituitary development.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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