Tristetraprolin is a novel regulator of BDNF

Brain-derived neurotrophic factor (BDNF) regulates multiple biological processes ranging from central nervous system development and function to neuroinflammation and myogenic differentiation and repair. While coordination of BDNF levels is central in determining the biological outcome, mechanisms involved in controlling BDNF levels are not fully understood. Here we find that both short (BDNF-S) and long (BDNF-L) BDNF 3'UTR isoforms contain conserved adenylate- and uridylate rich elements (AREs) that may serve as binding sites for RNA-binding proteins (ARE-BPs). We demonstrate that ARE-BPs tristetraprolin (TTP) and its family members butyrate response factor 1 (BRF1) and 2 (BRF2) negatively regulate expression from both BDNF-S and BDNF-L containing transcripts in several cell-lines and that interaction between TTP and AU-rich region in proximal 5' end of BDNF 3' UTR is direct. In line with the above, endogenous BDNF mRNA co-immunoprecipitates with endogenous TTP in differentiated mouse myoblast C2C12 cells and TTP overexpression destabilizes BDNF-S containing transcript. Finally, RNAi- mediated knock-down of TTP increases the levels of endogenous BDNF protein in C2C12 cells. Our findings uncover TTP as a novel regulator of BDNF assisting future studies in different physiological and pathological contexts.