Analysis of aromatase/estrogen system in the age-related diseases by developmental engineering techniques

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Aromatase knockout (ArKO) mouse which exhibits complete loss of capacity for estrogen biosynthesis was prepared and examined for sexual differentiation of the brain. The results indicated obvious abnormalities in the sexual motivation, sexual behaviors, aggressiveness, and parental behaviors of ArKO mice. Aromatae in the mouse brain shows a transient peak of expression at the perinatal period critaical for sexual differentiation of the brain, and is localized in nerve cells of the specific brain regions, namely of the reproductive center of hypothalamus, preoptic area, and amygdala. To elucidate the regulatory mechanism of neuron-specific, region-specific, and developmental stage-specific expression of brain aromatase, a hybrid gene cosisting of the brain-specific promoter region of aromatase gene and a beta-galactosidase structural gene was introduced into a mouse oocyte to create a transgenic (TG) mouse, and expression of beta-galactosidase in the brain of the TG mouse was analyzed. … More Conseqeuntly, at least 6.4 kb promoter region upstream from the brain-specific exon 1 of mouse aromatase gene is essential for neuron-specific, region-specific, and developmental stage-specific expression of brain aromatase.Human aromatase gene is tissue-specifically regulated by alternative use of multiple exons 1 and promoters. To elucidate the regulatory mechanism of tissue-specific expression, a humanized TG mouse carrying a reporter gene (beta-galactosidase) controlled by the multiple promoters of human aromatase gene was prepared. In this TG mouse the reporter gene was expressed in ovarian granulosa cells, testis Leydig cells, placenta, fetus liver, skin bone' artery, adipose tissue. The distribution of expression of the reporter gene in the TG mouse was exactly the same as that of the aromatase gene in human. Furthermore, the tissue-preference of alternative exons 1a, 1b, 1c, and 1d in the tissues of the TG mouse was also the same as that of human. These results indicate that this humanized TG mouse is a useful model animal for analysis of tissue-specific expression of human aromatae gene. Less