PITUITARY-DIRECTED LEUKEMIA INHIBITORY FACTOR TRANSGENE FORMS RATHKESCLEFT CYSTS AND IMPAIRS ADULT PITUITARY-FUNCTION - A MODEL FOR HUMAN PITUITARY RATHKES CYSTS

Leukemia inhibitory factor (LIF) and LIF receptors are expressed in ad enohypophyseal cells and LIF regulates pituitary hormone transcription and cell replication in vitro, Therefore, transgenic mice expressing pituitary-directed LIF driven by the rat growth hormone (GH) promoter were generated to evaluate the impact of LIF on pituitary development, Three founders were established with diminished linear growth and bod y weight (57-65% of wild type [WT]), and intense anterior pituitary LI F immunoreactivity, Cystic cavities observed in pituitary anterior lob es were lined by cuboidal, ciliated epithelial cells, focally immunopo sitive for cytokeratin and S-100 protein and immunonegative for adenoh ypophyseal hormones, Transgenic pituitaries showed decreased GH (40%) and prolactin (PRL) (26%) cells, and decreased GH and PRL mRNAs by in situ hybridization. ACTH cells increased 2.2-fold, whereas gonadotroph s and thyrotrophs were unchanged, Serum GH was undetectable (< 0.78 ng /ml), PRL levels were one third of WT (P < 0.05), IGF-I levels were 30 % of WT (P < 0.001), and T4 was normal. 10 human pituitary Rathke's cy sts studied all showed conclusive LIF immunoreactivity in cyst-lining cells, Thus, intrapituitary murine LIF overexpression causes cystic in vaginations from the anterior wall of Rathke's cleft, suggesting faile d differentiation of Rathke's epithelium to hormone-secreting cells, A rrested murine pituitary maturation with formation of pituitary Rathke 's cleft cysts, GH deficiency, and short stature provide a model to st udy human Rathke's cyst pathogenesis.