5'-flanking sequences of the human HPRT gene direct neuronal expression in the brain of transgenic mice.
Total deficiency of hypoxanthine phosphoribosyltransferase (HPRT) in humans 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 determine if cis-acting DNA elements play a role in the tissue-differential pattern of expression, we generated transgenic mice carrying different 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 contains essential information to direct beta-galactosidase expression preferentially to the basal ganglia, cerebral cortex, hippocampus, and several 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 not only in conferring neuronal specificity but also in repressing transgene expression in non-neuronal tissues. These studies provide molecular insight into the mechanism of increased HPRT expression in the brain.
Rincón-Limas
D E
DE
Department of Neurology, Baylor College of Medicine, Houston, TX 77030.
Geske
R S
RS
Xue
J J
JJ
Hsu
C Y
CY
Overbeek
P A
PA
Patel
P I
PI
D000818:Animals; D001483:Base Sequence; D001923:Brain Chemistry / Q000502:physiology*; D004247:DNA / Q000032:analysis; D005786:Gene Expression Regulation; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012313:RNA / Q000032:analysis
D012313:RNA; D004247:DNA; D007041:Hypoxanthine Phosphoribosyltransferase