REGULATION OF CELL-TYPE-SPECIFIC EXPRESSION OF LACZ BY THE 5'-FLANKING REGION OF MOUSE GAD67 GENE IN THE CENTRAL-NERVOUS-SYSTEM OF TRANSGENIC MICE

The transcriptional regulation of the murine gene encoding the 67-kDa form of glutamic acid decarboxylase (GAD67) was studied by beta-galact osidase histochemistry in transgenic mice carrying fusion genes betwee n progressively longer portions of the 5'-upstream regulatory region o f GAD67 and E. coli lacZ. No expression was detected in brains of mice carrying 1.3 kb of upstream sequences including a housekeeping and tw o conventional promoters, and two negative regulatory elements with ho mology to known silencers. In mice carrying the same portion of the pr omoter region plus the first intron, lacZ expression in the adult cent ral nervous system was found in few, exclusively neuronal sites. The n umber of correctly stained GABAergic centres increased dramatically wi th increasing the length of the 5'-upstream region included in the con struct which suggests that multiple putative spatial enhancers are loc ated in this region. Their action is influenced by epigenetic mechanis ms that may be due to site-of-integration and transgene copy-number ef fects. Additional cis-acting elements are needed to obtain fully corre ct expression in all GABAergic neurons of the adult central nervous sy stem.