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

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

doi:10.1038/ncomms9888

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

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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.

Original language	English (US)
Article number	8888
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9888
State	Published - Nov 20 2015

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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title = "Novel RNA-and FMRP-binding protein TRF2-S regulates axonal mRNA transport and presynaptic plasticity",

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.",

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

note = "Funding Information: This work was supported by the Intramural Research Program of the National Institute on Aging and by a grant to M.P.M. from the Glenn Foundation for Medical Research. We thank Haiyang Jiang, Min Geol Joo, Elin Lehrmann and William Wood for technical support, and Erez Eitan, Sana Siddiqui and Su Zhang for critical comments on the manuscript. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = nov,

day = "20",

doi = "10.1038/ncomms9888",

language = "English (US)",

volume = "6",

journal = "Nature Communications",

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T1 - Novel RNA-and FMRP-binding protein TRF2-S regulates axonal mRNA transport and presynaptic plasticity

AU - Zhang, Peisu

AU - Abdelmohsen, Kotb

AU - Liu, Yong

AU - Tominaga-Yamanaka, Kumiko

AU - Yoon, Je Hyun

AU - Ioannis, Grammatikakis

AU - Martindale, Jennifer L.

AU - Zhang, Yongqing

AU - Becker, Kevin G.

AU - Yang, In Hong

AU - Gorospe, Myriam

AU - Mattson, Mark P.

N1 - Funding Information: This work was supported by the Intramural Research Program of the National Institute on Aging and by a grant to M.P.M. from the Glenn Foundation for Medical Research. We thank Haiyang Jiang, Min Geol Joo, Elin Lehrmann and William Wood for technical support, and Erez Eitan, Sana Siddiqui and Su Zhang for critical comments on the manuscript. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/11/20

Y1 - 2015/11/20

N2 - 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.

AB - 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.

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

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