Accession Number : AD1011483


Title :   Regulatory Mechanisms Involved in the Expression of Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor


Descriptive Note : Technical Report


Corporate Author : Uniformed Services University Of The Health Sciences Bethesda United States


Personal Author(s) : Bishop,John F


Full Text : http://www.dtic.mil/dtic/tr/fulltext/u2/1011483.pdf


Report Date : 01 Mar 1996


Pagination or Media Count : 176


Abstract : Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) exert potent neurotrophic actions on several neuronal populations and are capable of protecting dopaminergic neurons in the brain from neurotoxin-induced degeneration. While many of the studies conducted to date have focused on the postsynaptic effects of BDNF and GDNF, very few have addressed the regulatory mechanisms involved in the expression of these factors. In phase 1 of the project, five alternate first exons contained in the rat BDNF gene, including a novel one termed exon la, were isolated and found to be individually spliced to a common protein coding exon resulting in five separate transcripts differing at their 5' ends. Subsequent experiments conducted in phase 2 indicated that expression of these five transcripts is differentially regulated in the brain regions investigated (substantia nigra, striatum, hippocampus and cerebellum), indicating differential utilization of alternate promoters. In addition, it was determined that long-term BDNF mRNA expression in the striatum was not altered by destruction of the presynaptic dopaminergic pathway and that calcium is a prominent second messenger involved in the regulation of BDNF and GDNF gene transcription. Treatment of C6 glioma cells with A23187, forskolin + isobutylmethylxanthine (IBMX) or 12-0-tetradecanoyl-phorbol-13-acetate (TPA) to elevate intracellular calcium, cAMP or protein kinase C activity, respectively, led to varying elevations in BDNF and GDNF transcript levels. A23187 treatment produced greater than 5-fold elevations in all of the mRNA species measured, which was largely attributed to an increased rate of transcription initiation. Forskolin + IBMX or TPA treatments lead to 2-fold and 3-fold increases in BDNF and GDNF mRNA levels, respectively.


Descriptors :   gene expression , Transcription (Genetics) , brain , wounds and injuries , rna (ribonucleic acids) , receptor sites (physiology) , Parkinsons disease


Distribution Statement : APPROVED FOR PUBLIC RELEASE