Dendritic targeting of short and long 3' UTR BDNF mRNA is regulated by BDNF or NT-3 and distinct sets of RNA-binding proteins.

Annalisa Vicario,Andrea Colliva,Claudia Colombrita,Enrico Tongiorgi,Laetitia Davidovic,Alberto Pallavicini,Barbara Bardoni,Antonia Ratti,Kevin R Jones,Łukasz Gricman,Gabriele Baj

doi:10.3389/fnmol.2015.00062

Abstract

Sorting of mRNAs in neuronal dendrites relies upon inducible transport mechanisms whose molecular bases are poorly understood. We investigated here the mechanism of inducible dendritic targeting of rat brain-derived neurotrophic factor (BDNF) mRNAs as a paradigmatic example. BDNF encodes multiple mRNAs with either short or long 3′ UTR, both hypothesized to harbor inducible dendritic targeting signals. However, the mechanisms of sorting of the two 3′ UTR isoforms are controversial. We found that dendritic localization of BDNF mRNAs with short 3′ UTR was induced by depolarization and NT3 in vitro or by seizures in vivo and required CPEB-1, -2 and ELAV-2, -4. Dendritic targeting of long 3′ UTR was induced by activity or BDNF and required CPEB-1 and the relief of soma-retention signals mediated by ELAV-1, -3, -4, and FXR proteins. Thus, long and short 3′ UTRs, by using different sets of RNA-binding proteins provide a mechanism of selective targeting in response to different stimuli which may underlay distinct roles of BDNF variants in neuronal development and plasticity.

Highlights

Subcellular compartmentalization of mRNAs is a mechanism enabling local synthesis of proteins required for neuronal development and plasticity such as brain-derived neurotrophic factor (BDNF; Tongiorgi et al, 1997; Steward and Schuman, 2001; Soule et al, 2006; Rodriguez et al, 2008; Tongiorgi, 2008; Martin and Ephrussi, 2009)
We previously showed that neuronal depolarization and BDNF induce dendritic localization of BDNF mRNA in vitro (Tongiorgi et al, 1997; Righi et al, 2000), it remained undetermined if other neurotrophins can induce BDNF mRNA localization in dendrites
Activity- and NT3-dependent dendritic targeting of 3 UTR short requires cytoplasmatic polyadenylation element binding proteins (CPEBs)-1,2 and embryonic lethal abnormal vision like proteins (ELAVs)-2,4 while dendritic targeting of long 3 UTR relies on a more complex mechanism. This includes BDNF-dependent release of somaretention signals mediated by ELAV-1,3,4, Fragile X mental retardation protein (FMRP) and FXRP2, and KCl/BDNF-activation of inducible targeting signals mediated by CPEB-1

Summary

INTRODUCTION

Subcellular compartmentalization of mRNAs is a mechanism enabling local synthesis of proteins required for neuronal development and plasticity such as brain-derived neurotrophic factor (BDNF; Tongiorgi et al, 1997; Steward and Schuman, 2001; Soule et al, 2006; Rodriguez et al, 2008; Tongiorgi, 2008; Martin and Ephrussi, 2009). Our alternative model is based on a tripartite combinatorial mechanism in which “selector” signals are located in the 5 UTR (for dendrite or soma destination), a constitutively active dendritic targeting element (DTE) mediated by Translin in the CDS, and activity-dependent DTEs harbored in both long and short 3 UTRs (Pattabiraman et al, 2005; Chiaruttini et al, 2008, 2009; Aliaga et al, 2009; Baj et al, 2011, 2013). We investigated the dendritic targeting mechanism of BDNF transcripts with long or short 3 UTR, demonstrating selective induction by BDNF or NT-3, respectively thanks to interactions with distinct sets of RBPs

MATERIALS AND METHODS

RESULTS

DISCUSSION