Novel RNA- and FMRP-binding protein TRF2-S regulates axonal mRNA transport and presynaptic plasticity.

Peisu Zhang,Jennifer L Martindale,Kumiko Tominaga-Yamanaka,Kotb Abdelmohsen,Myriam Gorospe,Grammatikakis Ioannis,In Hong Yang,Mark P Mattson,Yongqing Zhang,Kevin G Becker,Je-Hyun Yoon,Yong Liu

doi:10.1038/ncomms9888

Abstract

Despite considerable evidence that RNA-binding proteins (RBPs) regulate mRNA transport and local translation in dendrites, roles for axonal RBPs are poorly understood. Here we demonstrate that a non-telomeric isoform of telomere repeat-binding factor 2 (TRF2-S) is a novel RBP that regulates axonal plasticity. TRF2-S interacts directly with target mRNAs to facilitate their axonal delivery. The process is antagonized by fragile X mental retardation protein (FMRP). Distinct from the current RNA-binding model of FMRP, we show that FMRP occupies the GAR domain of TRF2-S protein to block the assembly of TRF2-S–mRNA complexes. Overexpressing TRF2-S and silencing FMRP promotes mRNA entry to axons and enhances axonal outgrowth and neurotransmitter release from presynaptic terminals. Our findings suggest a pivotal role for TRF2-S in an axonal mRNA localization pathway that enhances axon outgrowth and neurotransmitter release.

Highlights

Despite considerable evidence that RNA-binding proteins (RBPs) regulate mRNA transport and local translation in dendrites, roles for axonal RBPs are poorly understood
To identify global in vivo interactions of telomere repeat-binding factor 2 (TRF2)-S with mRNAs in neurons, we initiated the study with a procedure known as an RNP immunoprecipitation (RIP) assay[29]
The findings suggested that occupation of the TRF2-S glycine– arginine-rich (GAR) domain by fragile X mental retardation protein (FMRP) competitively inhibits RNA binding to the GAR domain of TRF2-S, thereby blocking the TRF2-S–RNP assembly (Fig. 3f)

Summary

Introduction

Despite considerable evidence that RNA-binding proteins (RBPs) regulate mRNA transport and local translation in dendrites, roles for axonal RBPs are poorly understood. Our findings suggest a pivotal role for TRF2-S in an axonal mRNA localization pathway that enhances axon outgrowth and neurotransmitter release. Recent findings suggest that axons may deploy local translation of mRNAs to regulate axon outgrowth and regeneration, and synapse formation and remodelling[5,6,7,8]. Among neuronal RBPs, fragile X mental retardation protein (FMRP) has emerged as a pivotal regulator of local protein synthesis, especially in dendrites. Recent findings suggest that FMRP is located in axons of immature vertebrate neurons, where it may influence growth and neurotransmitter release[22] by inhibiting translation[23,24]. TRF2-S retains the N-terminal GAR domain but lacks the C-terminal Myb DNAbinding domain of TRF2, suggesting a plausible switch of binding preference from DNA to RNA

Methods

Results

Conclusion