TARGETED PITUITARY TUMORIGENESIS USING THE HUMAN THYROTROPIN BETA-SUBUNIT CHAIN PROMOTER IN TRANSGENIC MICE

We have generated transgenic mice that express the simian virus 40 (SV 40) large T antigen under the control of a 1109 bp 5'-flanking sequenc e of the human thyrotropin beta-subunit (TSH beta) gene. The hybrid ge ne, termed TTP-1, was microinjected into fertilized mouse eggs and 11 transgenic mice were obtained. One of the transgenic mice, a female, a phenotypical dwarf, developed a pituitary tumor and wasted away from 7 to 9 weeks after birth. To establish the transgenic mouse line, her ovaries were transferred to a normal female, whose ovaries were remove d beforehand. To examine the tissue specificity of transgene expressio n, mRNA of SV40 large T antigen was monitored in various tissues from the transgenic mice by the reverse transcriptase-polymerase chain reac tion analysis, and was detected only in the pituitary. Histological an d immunohistochemical analyses showed that the pituitary tumors of the transgenic mice were composed of poorly differentiated pituitary cell s expressing SV40 large T antigen. These results indicated that the 11 09 bp sequence of the human TSH beta 5'-flanking region is essential f or pituitary-specific expression of SV40 large T antigen in transgenic mice, which exhibited a dwarf phenotype and developed pituitary tumor s. The tumors were composed of undifferentiated cells and did not prod uce thyrotropin. These transgenic mice should provide a valuable anima l model for studying the pathogenesis of anterior pituitary tumors.