Rincón-Limas D E, Geske R S, Xue J J, Hsu C Y, Overbeek P A, Patel P I
Department of Neurology, Baylor College of Medicine, Houston, TX 77030.
J Neurosci Res. 1994 Jun 15;38(3):259-67. doi: 10.1002/jnr.490380304.
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.
人类次黄嘌呤磷酸核糖转移酶（HPRT）的完全缺乏会导致神经紊乱疾病——莱施-奈恩综合征。HPRT基因在所有组织中均以基础水平表达，但在大脑中表达水平更高，其相关性及机制尚不清楚。为了确定顺式作用DNA元件是否在组织差异表达模式中发挥作用，我们构建了携带与人β-半乳糖苷酶基因融合的人HPRT（hHPRT）启动子不同序列的转基因小鼠。我们发现，hHPRT启动子的一个1.6 kb片段包含将β-半乳糖苷酶表达优先导向基底神经节、大脑皮层、海马体及前脑其他几个区域的必要信息。1.6 kb片段内至少有两个元件似乎是神经元表达所必需的。一个182 bp元件（hHPRT-NE）就是其中之一，它不仅参与赋予神经元特异性，还参与抑制非神经元组织中的转基因表达。这些研究为大脑中HPRT表达增加的机制提供了分子层面的见解。
