DOMINANT DWARFISM IN TRANSGENIC RATS BY TARGETING HUMAN GROWTH-HORMONE (GH) EXPRESSION TO HYPOTHALAMIC GH-RELEASING FACTOR NEURONS

Expression of human growth hormone (hGH) was targeted to growth hormon e-releasing factor (GRF) neurons in the hypothalamus of transgenic rat s. This induced dominant dwarfism by local feedback inhibition of GRF. One line, bearing a single copy of a GRF-hGH transgene, has been char acterized in detail, and has been termed Tgr (for Transgenic growth-re tarded). hGH was detected by immunocytochemistry in the brain, restric ted to the median eminence of the hypothalamus. Low levels were also d etected in the anterior pituitary gland by radioimmunoassay. Transgene expression in these sites was confirmed by RT-PCR. Tgr rats had reduc ed hypothalamic GRF mRNA, in contrast to the increased GRF expression which accompanies GH deficiency in other dwarf rats. Endogenous GH mRN A, GH content, pituitary size and somatotroph cell number were also re duced significantly in Tgr rats. Pituitary adrenocorticotrophic hormon e (ACTH) and thyroid-stimulating hormone (TSH) levels were normal, but prolactin content, mRNA levels and lactotroph cell numbers were also slightly reduced, probably due to feedback inhibition of prolactin by the lactogenic properties of the hGH transgene. This is the first domi nant dwarf rat strain to be reported and will provide a valuable model for evaluating the effects of transgene expression on endogenous GH s ecretion, as well as the use of GH secretagogues for the treatment of dwarfism.