Woodbury D, Schaar D G, Ramakrishnan L, Black I B
Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
Brain Res. 1998 Aug 24;803(1-2):95-104. doi: 10.1016/s0006-8993(98)00627-1.
Glial cell line-derived neurotrophic factor (GDNF) is the most potent known survival factor for substantia nigra neurons, which degenerate in Parkinson's disease, for spinal motoneurons, which die in Lou Gehrig's disease (ALS), and for Purkinje neurons, the critical outflow cells of the cerebellum. Moreover, targeted deletion of the GDNF gene results in renal dysgenesis and abnormal development of the enteric nervous system. GDNF mRNA is expressed in a complex temporospatial pattern in the central nervous system and the periphery, consistent with these observations. To begin elucidating mechanisms regulating the pattern of expression of GDNF, we have cloned the human gene, and characterized the promoter. The promoter is highly GC rich, and lacks canonical CCAT-box and TATA-box motifs. It contains more than 12 binding sites for known transcription factors. These cis-elements have the potential to interact with factors regulating constitutive expression (Sp1) and developmental expression (bHLH). Moreover, the promoter contains sites for binding transcription factors which respond to environmental signals, including CREB, AP2, Zif/268, NFkB, and MRE-BP. Combinatorial actions of these transcription factors may account for the extraordinarily complex expression patterns of the GDNF gene. Importantly, we demonstrate that the hGDNF gene utilizes a promoter distinct from that identified in the rodent GDNF gene, a finding with ramifications for Parkinson's disease and ALS research.
胶质细胞源性神经营养因子（GDNF）是已知对黑质神经元最有效的存活因子，黑质神经元在帕金森病中会退化；它对脊髓运动神经元也很有效，脊髓运动神经元在卢伽雷氏病（肌萎缩侧索硬化症，ALS）中会死亡；此外，它对浦肯野神经元也有效，浦肯野神经元是小脑的关键传出细胞。而且，GDNF基因的靶向缺失会导致肾发育不全和肠神经系统发育异常。GDNF mRNA在中枢神经系统和外周以复杂的时空模式表达，与这些观察结果一致。为了开始阐明调节GDNF表达模式的机制，我们克隆了人类基因并对其启动子进行了表征。该启动子富含GC，缺乏典型的CCAT框和TATA框基序。它包含超过12个已知转录因子的结合位点。这些顺式元件有可能与调节组成型表达的因子（Sp1）和发育表达的因子（bHLH）相互作用。此外，启动子包含与环境信号应答的转录因子结合位点，包括CREB、AP2、Zif/268、NFkB和MRE-BP。这些转录因子的组合作用可能解释了GDNF基因极其复杂的表达模式。重要的是，我们证明人类GDNF基因利用的启动子与在啮齿动物GDNF基因中鉴定的启动子不同，这一发现对帕金森病和ALS研究具有重要意义。
