cDNA FOR HUMAN GDNF AND PROMOTER THEREFOR WHICH ALLOWS REGULATED AND CONSTITUTIVE EXPRESSION

摘要

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, 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 elucidate mechanisms regulating the pattern of expression of GDNF, the promoter for the human gene has been cloned and characterized. The promoter is highly GC rich, and lacks canonical CCAT-box and TATA-box motifs. It contains more than twelve binding sites for known transcription factors. These cis-elements exhibit 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 account for the extraordinarily complex expression patterns of the GDNF gene.