THE UPSTREAM SEQUENCE OF A NEW GROWTH DIFFERENTIATION FACTOR, MIDKINE(MK), MEDIATES DEVELOPMENTALLY-REGULATED LAC-Z GENE-EXPRESSION IN TRANSGENIC MICE/

Midkine (MK) is the product of a retinoic acid responsive gene, and is a heparin binding protein involved in the regulation of growth and di fferentiation. The 1.9 kb upstream region of MK gene was fused with th e bacterial beta-galactosidase gene (lac Z) and injected into fertiliz ed mouse eggs. The resulting transgenic mice were used to evaluate the in vivo transcriptional regulation through of the upstream region. Co mparison of the p-galactosidase expression and endogenous MK expressio n indicated that the temporal regulation of the transgene was similar to that of MK gene expression during mouse development. The transgene was neither expressed in the preimplantation period nor in 6.5-day emb ryos. Transgene expression was high and widely distributed on the 8.5t h day, became restricted on the 10.5th and 12.5th days, and thereafter almost confined to the kidney. Thus, the 1.9 kb upstream region accou nts for overall temporal regulation of MK gene expression, while there are some differences between the spatial regulation of the transgene expression and that of the endogenous MK gene expression. The transgen e was expressed in a few limited regions of the brain of 17 day old em bryos, and those sites consisted largely of matrix cells with columnar arrangements. These results suggests a role of MK in the brain develo pment, and MK activity may be involved in retinoic acid induced malfor mations of the central nervous system.