Development and differentiation of the mammary gland during puberty, pregnancy and lactation appears to be controlled by hormones and growth modulators. We have previously shown that an endogenous milk protein, the whey acidic protein (WAP), can participate in mammary development. Temporal deregulated expression in mammary tissue of transgenic mice resulted in abrogated mammary development. Ectopic expression of the WAP gene under the control of the MMTV-LTR resulted in impaired mammary development as well as neoplasias in the coagulation gland. No growth aberrations were observed in other expressing tissues, such as the salivary gland. This suggests that WAP exerts its growth modulatory effects in a cell-specific manner. The role of a given protein in tissue formation and differentiation processes can be evaluated using gain of function experiments in transgenic animals. However, the systems currently do not permit a spatial and temporal controlled activation and inactivation of transgenes. We established such a system using viral and bacterial tools. A binary system was built in which gene activity can be modulated using tetracycline. One line of mice carries a transgene composed of the human cytomegalovirus (HCMV) enhancer and the coding region for the DNA binding domain of the tetracycline repressor and the transcriptional activation domain VP16 from the Herpes simplex virus. The other line of transgenic mice carrier a reporter gene posed of tetracycline operators next to a minimal promoter and the luciferase gene. Upon breeding, double transgenic mice have an activated reporter gene. Activity of this reporter gene should be subject ot modulation by tetracycline as is currently investigated.
