The molecular basis of mammary-specific and developmentally and hormonally regulated gene expression is being studied through the analysis of the mouse whey acidic protein (WAP) gene in transgenic animals. Mammary- specific transcription elements and control elements conferring hormone regulation are located in the promoter/upstream region, and probably also within the body of the gene. It was shown that chromatin surrounding WAP transgenes can modify the response of transcription elements to hormonal and developmental stimuli. Matrix attachment regions can insulate transcription elements from such position effects, thereby emphasizing the role of chromatin domains in regulated gene expression. In continuation of establishing the mammary gland as a bioreactor, it was shown that regulatory elements from the mouse WAP gene are ideal for protein production in milk of transgenic swine and sheep. WAP regulatory elements are currently employed to produce human proteins such as tissue plasminogen activator, Protein C and glucocerebrosidase. It has been shown that precocious expression of WAP in mammary tissue during pregnancy can result in an abrogated mammary development and a milchlos phenotype. Ectopic expression of WAP in the salivary gland of transgenic mice did not interfere with development of the gland, suggesting that WAP may be a mammary-specific developmental/differentiation factor. A technology was developed to introduce DNA into somatic tissues of live animals using jet injection. This technology may be useful for generating somatic transgenics, for tumor cell ablation and for gene therapy.
