Transgenic mice with inducible dwarfism

Abstract

THE pituitary gland, composed of the anterior, intermediate and posterior lobe, represents a principal regulatory interface through which the central nervous system controls body physiology¹. The ontogeny of the growth hormone (GH) and prolactin (Prl) producing cells of the anterior pituitary has been analysed in transgenic mice, using the thymidine kinase obliteration system (TKO)^2,3. Cells expressing the herpes virus 1 thymidine kinase (HSV1-TK) gene acquire pharmacological sensitivity to synthetic nucleosides such as FIAU (l-(2-deoxy-2-fluoro-β-δ-arabinofuranosyl)-5-iodouracil), whose metabolites kill dividing cells. Consequently we created transgenic mice carrying the HSV1-TK gene under the control of either the rat growth hormone or the rat prolactin promoter. If transgenic mice expressing HSV1-TK in somatotropes (GH-producing cells) are treated with FIAU, they develop as dwarfs. The anterior pituitary in these animals is nearly devoid of both somatotropes and lactotropes (Prl-producing cells). By contrast, transgenic mice expressing HSV1-TK in the lactotropes, treated with FIAU, have anatomically and histologically normal pituitaries. Because toxicity depends on cell division, we conclude that Prl expression and lactotrope differentiation are post-mitotic events. These results indicate that both somatotropes and lactotropes derive from a common GH-expressing stem-somatotrope. Unexpectedly, the stemsomatotrope is still present in the adult animal and is capable of repopulating the pituitaries of treated animals with mature GH and Prl producing cells.