5'-FLANKING SEQUENCES OF THE HUMAN HPRT GENE DIRECT NEURONAL EXPRESSION IN THE BRAIN OF TRANSGENIC MICE

Total deficiency of hypoxanthine phosphoribosyltransferase (HPRT) in h umans causes the neurological disorder Lesch-Nyhan syndrome. The HPRT gene is expressed at basal levels in all tissues but at higher levels in the brain, the relevance and mechanism of which is unknown. To dete rmine if cis-acting DNA elements play a role in the tissue-differentia l pattern of expression, we generated transgenic mice carrying differe nt sequences of the human HPRT (hHPRT) promoter fused to the bacterial lacZ gene. We show that a 1.6 kb fragment of the hHPRT promoter conta ins essential information to direct beta-galactosidase expression pref erentially to the basal ganglia, cerebral cortex, hippocampus, and sev eral other areas of the forebrain. At least two elements within the 1. 6 kb fragment appear to be required for neuronal expression. A 182 bp element (hHPRT-NE) represents one of these sequences and is involved n ot only in conferring neuronal specificity but also in repressing tran sgene expression in non-neuronal tissues. These studies provide molecu lar insight into the mechanism of increased HPRT expression in the bra in. (C) 1994 Wiley-Liss, Inc.