IN-VIVO FUNCTIONAL-ANALYSIS OF THE MOUSE ESTROGEN-RECEPTOR GENE PROMOTER - A TRANSGENIC MOUSE MODEL TO STUDY TISSUE-SPECIFIC AND DEVELOPMENTAL REGULATION OF ESTROGEN-RECEPTOR GENE-TRANSCRIPTION

Understanding the molecular and morphological basis of estrogen respon siveness in the various tissues and organs that make up an adult organ ism and its onset during ontogenesis requires identification of the ge netic controls that determine timed expression of the estrogen recepto r (ER) gene in multiple cell types. With this goal in mind, we describ e here the results of the functional analysis of the mouse (m) ER gene promoter, carried out in vivo in transgenic mice. The mER gene promot er was cloned and spliced to the coding sequence of the bacterial lacZ gene (fused to the nuclear localization signal of SV40 large T: nls-b eta-GAL) and then stably reintegrated into the genome of mice. Analysi s of beta-GAL mRNA and protein expression in multiple organs of both f emale and male transgenic animals was then performed. Results show tha t the transgenic mER promoter, much like the endogenous one, is active in several organs and tissues of adult female and male mice. The firs t 0.4 kilobases of 5'-flanking DNA (up to -364) are sufficient to dire ct widespread expression of the transgene in mouse organs. This indica tes that genetic elements functional in various cell types are include d in this segment. Furthermore, the first exon and intron of the mER g ene are necessary to achieve sexually dimorphic expression of the tran sgene in neurons located at specific sites within the central nervous system. These mER promoter transgenic mice will be useful in mapping e strogen-responsive cell types under different physiological and pathol ogical conditions in vivo, in defining ontogenesis of estrogen action in the mouse, and in studying the mechanisms that regulate ER gene tra nscription.