Novel structure of the human GDNF gene.
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.
Woodbury
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Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA. woodburydl@aol.com
Schaar
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Ramakrishnan
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Black
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D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D018387:Codon, Initiator / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D017874:Immediate-Early Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
D018387:Codon, Initiator; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C495039:GDNF protein, human; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D017874:Immediate-Early Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D014157:Transcription Factors