PITUITARY-DIRECTED LEUKEMIA INHIBITORY FACTOR TRANSGENE CAUSES CUSHINGS-SYNDROME - NEURO-IMMUNE-ENDOCRINE MODULATION OF PITUITARY DEVELOPMENT

Leukemia inhibitory factor (LIF) regulates the mature hypothalamic-pit uitary-adrenal axis in vivo. In vitro, LIF determines corticotroph cel l proliferation and induces POMC transcription. To explore LIF action on pituitary development, transgenic mice expressing LIF driven by the pituitary glycoprotein hormone alpha-subunit (alpha GSU) promoter wer e generated. Transgenic mice exhibited dwarfism with low IGF-I (29 +/- 9 ng/ml vs, wild type (WT) 137 +/- 16 ng/ml; P < 0.001), hypogonadism with low FSH (0.04 +/- 0.023 ng/ml vs. WT 0.63 +/- 0.18 ng/ml; P < 0. 001), and Cushingoid features of thin skin and truncal obesity with el evated cortisol levels (86 +/- 22 ng/ml vs. WT 50 +/- 14 ng/ml; P = 0. 002). Their pituitary glands showed corticotroph hyperplasia, striking somatotroph and gonadotroph hypoplasia, and multiple Rathke-like cyst s lined by ciliated cells. LIF, overexpressed in Rathke's pouch at emb ryonal day 10, diverts the differentiation stream of hormone-secreting cells toward the corticotroph lineage and ciliated nasopharyngeal-lik e epithelium. Thus, inappropriate expression of LIF, a neuro-immune in terfacing cytokine, plays a key role in the terminal differentiation e vents of pituitary development and mature pituitary function.