Tristetraprolin is a novel regulator of BDNF

Anmol Kumar,Johan Peränen,Kärt Varendi,Jaan-Olle Andressoo

doi:10.1186/2193-1801-3-502

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-3-502) contains supplementary material, which is available to authorized users.

Highlights

Brain-derived neurotrophic factor (BDNF) is involved in a wide range of developmental, functional and pathological processes in the central nervous system (CNS) (Nagahara and Tuszynski 2011; Kirschenbaum and Goldman 1995; Cohen-Cory et al 2010; Bamji et al 2006; Nieto et al 2013; Mu et al 1999)
Myogenic differentiation of C2C12 mouse skeletal myoblast cells was induced by replacing growth medium with differentiation medium (DM) containing DMEM supplemented with 2% horse serum (HS; B15-021, PAA) (Miura et al 2012) and 100 μg/ml Normocin
Two of the five AUUUA motifs were present in BDNF-S, while three AUUUA motifs were only present in BDNF-L (Figure 1, Additional file 1: Figure S2)

Summary

Introduction

BDNF is involved in a wide range of developmental, functional and pathological processes in the central nervous system (CNS) (Nagahara and Tuszynski 2011; Kirschenbaum and Goldman 1995; Cohen-Cory et al 2010; Bamji et al 2006; Nieto et al 2013; Mu et al 1999). Reduction of BDNF levels by 50% in BDNF knock-out heterozygous mice is associated with a range of phenotypes in the CNS (Lyons et al 1999; Dluzen et al 2002; Abidin et al 2006; Abidin et al 2008).

Methods

Results

Conclusion