A MYELIN PROTEOLIPID PROTEIN-LACZ FUSION PROTEIN IS DEVELOPMENTALLY-REGULATED AND TARGETED TO THE MYELIN MEMBRANE IN TRANSGENIC MICE

Transgenic mice were generated with a fusion gene carrying a portion o f the murine myelin proteolipid protein (PLP) gene, including the firs t intron, fused to the E. coli LacZ gene. Three transgenic lines were derived and all lines expressed the transgene in central nervous syste m white matter as measured by a histochemical assay for the detection of beta-galactosidase activity. PLP-LacZ transgene expression was regu lated in both a spatial and temporal manner, consistent with endogenou s PLP expression. Moreover, the transgene was expressed specifically i n oligodendrocytes from primary mixed glial cultures prepared from tra nsgenic mouse brains and appeared to be developmentally regulated in v itro as well. Transgene expression occurred in embryos, presumably in pre- or nonmyelinating cells, rather extensively throughout the periph eral nervous system and within very discrete regions of the central ne rvous system. Surprisingly, beta-galactosidase activity was localized predominantly in the myelin in these transgenic animals, suggesting th at the NH2-terminal 13 amino acids of PLP, which were present in the P LP-LacZ gene product, were sufficient to target the protein to the mye lin membrane. Thus, the first half of the PLP gene contains sequences sufficient to direct both spatial and temporal gene regulation and to encode amino acids important in targeting the protein to the myelin me mbrane.