Schaar D G, Sieber B A, Sherwood A C, Dean D, Mendoza G, Ramakrishnan L, Dreyfus C F, Black I B
Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854-5635.
Exp Neurol. 1994 Dec;130(2):387-93. doi: 10.1006/exnr.1994.1218.
The recent discovery of glial cell line-derived neurotrophic factor (GDNF) identified a novel trophin that selectively increases survival of substantia nigra dopaminergic neurons, which degenerate in Parkinson's disease. Our previous studies indicated that GDNF RNA can be amplified from cultured rat nigral type 1 astrocytes and from rat striatum in vivo, implying local as well as target trophic support. The current study establishes the regional pattern of GDNF RNA expression in adult human brain. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed the highest expression of GDNF mRNA in the human caudate, with low levels in the putamen and no detectable message in the nigra, suggesting that GDNF is a target-derived factor in humans. We also report the isolation of two additional GDNF-related cDNAs, termed astrocyte-derived trophic factors (ATF), which apparently result from differential RNA processing. Sequence analysis of rat ATF-1 revealed a 78-bp deletion corresponding to a loss of 26 amino acids within the prepro region of the predicted GDNF protein. The RNA processing events responsible for ATF-1 formation in rat brain are conserved in humans; we report the isolation of a full-length human ATF-1 homologue. We identified a second alternative transcript, human ATF-2; the transcript encodes a protein which differs in its first 18 amino acids from the predicted mature GDNF and ATF-1 proteins and shares the terminal 115 residues with the other two forms. To begin assessing the biologic significance of multiple transcript expression we characterized the actions of COS-expressed GDNF and ATF-1 cDNAs.(ABSTRACT TRUNCATED AT 250 WORDS)
最近发现的胶质细胞源性神经营养因子（GDNF）是一种新的神经营养因子，它能选择性地提高黑质多巴胺能神经元的存活率，而这些神经元在帕金森病中会发生退化。我们之前的研究表明，GDNF RNA可从培养的大鼠黑质1型星形胶质细胞以及大鼠纹状体中扩增出来，这意味着存在局部和靶源性的营养支持。本研究确定了GDNF RNA在成人大脑中的区域表达模式。逆转录聚合酶链反应（RT-PCR）分析显示，GDNF mRNA在人类尾状核中表达最高，在壳核中表达水平较低，在黑质中未检测到信号，这表明GDNF在人类中是一种靶源性因子。我们还报告了另外两个与GDNF相关的cDNA的分离，它们被称为星形胶质细胞源性营养因子（ATF），这显然是由不同的RNA加工产生的。大鼠ATF-1的序列分析显示，在预测的GDNF蛋白前原区有一个78 bp的缺失，对应于26个氨基酸的缺失。在大鼠脑中负责ATF-1形成的RNA加工事件在人类中是保守的；我们报告了全长人类ATF-1同源物的分离。我们鉴定出了第二种可变转录本，即人类ATF-2；该转录本编码的蛋白质在其前18个氨基酸上与预测的成熟GDNF和ATF-1蛋白不同，并与其他两种形式共享末端115个残基。为了开始评估多种转录本表达的生物学意义，我们对COS表达的GDNF和ATF-1 cDNA的作用进行了表征。（摘要截短至250字）
