CYTOCHROME-P450 1A1 PROMOTER AS A GENETIC SWITCH FOR THE REGULATABLE AND PHYSIOLOGICAL EXPRESSION OF A PLASMA-PROTEIN IN TRANSGENIC MICE

Transgenic and gene knockout techniques allow for in vivo study of the consequences of adding or subtracting specific genes. However, in som e instances, such as the study of lethal mutations or of the physiolog ical consequences of changing gene expression, turning on and off an i ntroduced gene at will would be advantageous. We have used cytochrome p450 1A1 promoter to drive expression of the human apolipoprotein E (a poE) gene in transgenic mice. In six independent lines, robust express ion of the transgene depended upon injection of the inducer beta-napht hoflavone, whereas the seventh line had high basal expression that was augmented further by the inducer. The low level of basal expression i n an inducer-dependent line was confirmed upon breeding the transgene onto the hypercholesterolemic apoE-deficient background. In the basal state transgene expression was physiologically insignificant, as these mice were as hypercholesterolemic as their nontransgenic apoE-deficie nt littermates. When injected with the inducer, plasma cholesterol lev els of the transgenic mice decreased dramatically as apoE expression w as induced to yield greater than physiological levels in plasma. The i nducer could pass transplacentally from an injected mother to her fetu ses with concomitant induction of fetal transgene mRNA. Inducer could also pass via breast milk from an injected mother to her suckling neon atal pups, giving rise to the induction of human apoE in neonate plasm a. These finding suggest a strategy to temporarily ameliorate genetic deficiencies that would otherwise lead to fetal or neonatal lethality.