Regulation of brain-derived neurotrophic factor in the adult mouse brain

by Malkovska, Irena.

In the adult central nervous system (CNS) brain-derived neurotrophic factor (BDNF) has been implicated in neuroprotection and synaptic plasticity among other functions. However, relatively little is known of its regulation. In this thesis, we attempted to learn more about BDNF regulation by means of: an in situ hybridization study of the four distinct untranslated exons in the adult mouse brain; use of transgenic animals to define BDNF promoter regions; and use of comparative genomics to identify evolutionarily conserved regions of BDNF. The in situ hybridization study suggests that the four distinct BDNF promoters are differentially regulated and that neighboring promoters are coregulated. Also it appears that all four promoters function in most of the same nuclei of the adult CNS. Inspite of the large size of the transgenic constructs used in this study specific to exons 1/2 and 3/4 (11.4 kb and 16 kb respectively), they were insufficient to mediate endogenous-like BDNF expression in the adult CNS. v However, this study suggests that these regions may drive endogenous-like expression in a subset of nuclei (random chance integration cannot however be ruled out). The bioinformatics study revealed 9 highly conserved elements that are good candidates for cis-regulatory elements of BDNF. In conclusion, the regulation of the BDNF gene appears far more complicated than was previously predicted. vi