A 6-KB UPSTREAM REGION OF THE HUMAN TRANSTHYRETIN GENE CAN DIRECT DEVELOPMENTAL, TISSUE-SPECIFIC, AND QUANTITATIVELY NORMAL EXPRESSION IN TRANSGENIC MOUSE

To ascertain whether a 6-kb upstream region of the human transthyretin (TTR) gene contains the cis-element(s) required for proper specificit y and level of expression, transgenic mice carrying the human mutant T TR gene containing either 6-kb (6.0-hMet30) or 0.6-kb (0.6-hMet30) of the upstream region were produced and studied. The 6.0-hMet30 gene was expressed in the yolk sac, liver, and choroid plexus, where the mouse endogenous TTR gene is also expressed. In contrast, expression of the 0.6-hMet30 gene was restricted to the yolk sac and liver. The express ion levels of the 6.0-hMet30 gene in the liver and serum were similar to those of the mouse TTR gene, and about 10-fold those of the 0.6-hMe t30 gene. Before birth, the developmental profiles of the expression o f both transgenes in each tissue were similar to those of the mouse TT R gene. However, the expression levels of the 6.0-hMet30 gene in the l iver and serum increased after birth to reach adult levels at an age o f 4 weeks, while expression of the 0.6-hMet30 gene remained at a low l evel after birth. These results suggest that the 6-kb upstream sequenc e contains the cis-elements required for developmental, tissue-specifi c, and quantitatively normal expression.