Akita S, Readhead C, Stefaneanu L, Fine J, Tampanaru-Sarmesiu A, Kovacs K, Melmed S
Department of Medicine, Cedars-Sinai Research Institute, University of California, Los Angeles School of Medicine, Los Angeles, California 90048, USA.
J Clin Invest. 1997 May 15;99(10):2462-9. doi: 10.1172/JCI119430.
Leukemia inhibitory factor (LIF) and LIF receptors are expressed in adenohypophyseal 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 body weight (57-65% of wild type [WT]), and intense anterior pituitary LIF immunoreactivity. Cystic cavities observed in pituitary anterior lobes were lined by cuboidal, ciliated epithelial cells, focally immunopositive for cytokeratin and S-100 protein and immunonegative for adenohypophyseal 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 gonadotrophs 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 cysts studied all showed conclusive LIF immunoreactivity in cyst-lining cells. Thus, intrapituitary murine LIF overexpression causes cystic invaginations from the anterior wall of Rathke's cleft, suggesting failed differentiation of Rathke's epithelium to hormone-secreting cells. Arrested murine pituitary maturation with formation of pituitary Rathke's cleft cysts, GH deficiency, and short stature provide a model to study human Rathke's cyst pathogenesis.
白血病抑制因子（LIF）及其受体在腺垂体细胞中表达，且LIF在体外可调节垂体激素转录和细胞复制。因此，构建了由大鼠生长激素（GH）启动子驱动、表达垂体定向LIF的转基因小鼠，以评估LIF对垂体发育的影响。建立了三只转基因小鼠，其线性生长和体重均降低（为野生型[WT]的57 - 65%），且垂体前叶LIF免疫反应性增强。在垂体前叶观察到的囊腔由立方状、纤毛上皮细胞衬里，这些细胞对细胞角蛋白和S - 100蛋白呈局灶性免疫阳性，对腺垂体激素呈免疫阴性。转基因垂体中生长激素（GH）细胞（减少40%）和催乳素（PRL）细胞（减少26%）数量减少，原位杂交显示GH和PRL mRNA水平降低。促肾上腺皮质激素（ACTH）细胞增加了2.2倍，而促性腺激素细胞和促甲状腺激素细胞未发生变化。血清GH检测不到（< 0.78 ng/ml），PRL水平为野生型的三分之一（P < 0.05），胰岛素样生长因子 - I（IGF - I）水平为野生型的30%（P < 0.001），而甲状腺素（T4）正常。对10例人垂体Rathke囊肿进行研究，结果显示囊肿衬里细胞均有明确的LIF免疫反应性。因此，垂体内LIF过表达导致Rathke裂前壁出现囊性内陷，提示Rathke上皮细胞未能分化为激素分泌细胞。小鼠垂体成熟停滞并形成垂体Rathke裂囊肿、GH缺乏和身材矮小，为研究人类Rathke囊肿发病机制提供了一个模型。
