The gonadotropin-releasing hormone receptor gene promoter directs pituitary-specific oncogene expression in transgenic mice

Our previous work has shown that 1.2 kb of the 5' flanking region of the mo use GnRH receptor (mGnRH-R) gene is sufficient to direct tissue-specific ex pression in vitro. In this study, me have used the cell-specific regulatory sequences of the mGnRH-R gene promoter to target the expression of the sim ian virus 40 virus T antigen (TAg) to the pituitary gland of transgenic mic e. A hybrid transgene, GnRH-R/TAg, was prepared using the - 1164/+52 region of the mGnRH-R gene and + 2533/+5234 sequences encoding the large T antige n of the simian Virus 40. Two founders developed tumors of apparent pituita ry origin at 44 (M28, female) and 50 (M25, male) days of age. M28 and M25 m ice were about 50% underweight, and their gonads were grossly underdevelope d compared with wild-type litter mates. A third male founder, M29, develope d a tumor at a later time (109 days). M29 was able to breed successfully an d stably transmit the GnRH-R/TAg transgene. Mice of the M29 transgene line developed tumors at 4-5 months of age. Gross examination showed that the tu mors extend from the sella and infiltrate into the inferior surface of the brain. In small tumors collected from young transgenic animals, normal pitu itary cells as well as transition areas of increasing cellular atypia are e vident. Frankly malignant cells are seen in all tumors. The pituitary tumor s express the alpha-, FSH beta-, and LH beta-subunits and the GnRH-R messen ger RNA, all markers of a gonadotrope but not of other anterior pituitary c ell lineages. In summary, our studies indicate that 1.2 kb of the 5'-flanki ng region of the mGnRH-R gene can be used to target expression specifically to the gonadotropes of the pituitary gland in transgenic mice. The GnRH-R gene promoter-directed expression appears to be cell-specific and results i n the formation of tumors that are primarily of gonadotropic origin.