Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2007) 14 P120

Department of Physiology, School of Medicine, University of Santiago de Compostela, santiago de Compostela, Spain.

RET is a tyrosine kinase receptor activated by GDNF, NTN, ART and PSPN through GFRa1,2, 3 and 4 respectively. Activation of the receptor elicits intracellular pathways such us Ras/MAPK and PI3K/AKT leading to differentiation and proliferation. Our group has previously shown that RET is expressed specifically in the somatotroph cell population within the pituitary gland, both in rats and in humans. We have also shown that, in absence of its ligand GDNF, RET induces activation of caspase 3 PKCd/JNK/c/EBPa and CREB, causing apoptosis in cell cultures. Cell death is dependent on Pit-1 and p53 induction. This findings confirm previous hypothesis and strongly indicate that RET acts as a dependence receptor. Now we provide evidence that the same biological and biochemical mechanisms work in vivo.

For doing so, we have used a model of lactotroph hyperplasia induced by estrogen administration in rat. Hyperplasic pituitary glands were infected with purified high-titer retroviruses encoding RET or the corresponding empty virus as control. Viral delivery was achieved by estereotaxia, injecting the retrovirus directly into the pituitary of living anesthetized rats. Following treatment and infection rats were sacrificed and pituitary weights recorded. As expected, estrogen treatment induced a marked increase in pituitary size. Interestingly, viral-mediated RET expression caused a significant reduction compared to mock-infected pituitaries (26.6+/− 1.8 mg vs 18.0+/− 1.0 mg), restoring pituitary weight to values similar to pituitaries not treated with estrogens. We were able to detect RET expression in lactotrophs, suggesting that ectopic expression of the dependence receptor caused lactotroph cell death and hyperplasia reversal. Moreover, we show activation of the caspase 3-PKCd-JNK-c/EBPa-CREB apoptotic pathway, indicating that the same molecular events are elicited by RET in cell culture models and in vivo.

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