Locally translated mTOR controls axonal local translation in nerve injury

Terenzio, Marco; Koley, Sandip; Samra, Nitzan; Rishal, Ida; Zhao, Qian; Sahoo, Pabitra K.; Tlsty, Thea D.; Marvaldi, Letizia; Oses-Prieto, Juan A.; Forester, Craig M.; Gomes, Cynthia; Kalinski, Ashley L.; Pizio, Agostina Di; Doron-Mandel, Ella; Perry, Rotem Ben Tov; Koppel, Indrek; Twiss, Jeffery L.; Burlingame, Alma L.; Fainzilber, Mike

doi:10.1126/science.aan1053

Cited by 225 publications

(210 citation statements)

References 51 publications

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“…This would explain the downregulation observed from T3 to T14 and the subsequent upregulation at T21, when axons regenerate. Whether L-Pgds mRNA is locally translated in injured axons as it occurs for other proteins is not known (Koley, Rozenbaum, Fainzilber, & Terenzio, 2019;Spaulding & Burgess, 2017;Terenzio et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin D2 synthase modulates macrophage activity and accumulation in injured peripheral nerves

Forese

Pellegatta

Canevazzi

et al. 2019

Glia

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We have previously reported that prostaglandin D2 Synthase (L‐PGDS) participates in peripheral nervous system (PNS) myelination during development. We now describe the role of L‐PGDS in the resolution of PNS injury, similarly to other members of the prostaglandin synthase family, which are important for Wallerian degeneration (WD) and axonal regeneration. Our analyses show that L‐PGDS expression is modulated after injury in both sciatic nerves and dorsal root ganglia neurons, indicating that it might play a role in the WD process. Accordingly, our data reveals that L‐PGDS regulates macrophages phagocytic activity through a non‐cell autonomous mechanism, allowing myelin debris clearance and favoring axonal regeneration and remyelination. In addition, L‐PGDS also appear to control macrophages accumulation in injured nerves, possibly by regulating the blood–nerve barrier permeability and SOX2 expression levels in Schwann cells. Collectively, our results suggest that L‐PGDS has multiple functions during nerve regeneration and remyelination. Based on the results of this study, we posit that L‐PGDS acts as an anti‐inflammatory agent in the late phases of WD, and cooperates in the resolution of the inflammatory response. Thus, pharmacological activation of the L‐PGDS pathway might prove beneficial in resolving peripheral nerve injury.

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Section: Discussionmentioning

confidence: 99%

Prostaglandin D2 synthase modulates macrophage activity and accumulation in injured peripheral nerves

Forese

Pellegatta

Canevazzi

et al. 2019

Glia

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“…Though not always mechanistic, several high-throughput surveys of mRNAs in neural tissues have revealed that APA in brain results in longer 3 0 UTRs than other tissues (Fontes et al, 2017;Miura, Shenker, Andreu-Agullo, Westholm, & Lai, 2013). In neurons, longer 3 0 UTRs often result in selective translation of those mRNA isoforms in dendrites and axons (Ainsley, Drane, Jacobs, Kittelberger, & Reijmers, 2014;Terenzio et al, 2018) or reveal distal last exons that can localize transcripts to neurites (Taliaferro et al, 2016). We also believe that techniques like c-Tag-PAPERCLIP, in which epitope tags can be attached to RNA-binding proteins of interest in specific mouse cell types (Hwang et al, 2017), will increase the understanding of APA in brain and other tissues.…”

Section: Splicing and Polyadenylation Control Cgrp Expressionmentioning

confidence: 99%

Tissue‐specific mechanisms of alternative polyadenylation: Testis, brain, and beyond (2018 update)

MacDonald

2019

WIREs RNA

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Alternative polyadenylation (APA) is how genes choose different sites for 3′ end formation for mRNAs during transcription. APA often occurs in a tissue‐ or developmental stage‐specific manner that can significantly affect gene activity by changing the protein product generated, the stability of the transcript, its localization within the cell, or its translatability. Despite the important regulatory effects that APA has on tissue‐specific gene expression, only a few examples have been characterized mechanistically. In this 2018 update to our 2010 review, we examine mechanisms for the control of APA and update our understanding of the older mechanisms since 2010. We once postulated the existence of tissue‐specific factors in APA. However, while a few tissue‐specific polyadenylation factors are known, the emerging conclusion is that the majority of APA is accomplished by altering levels of core polyadenylation proteins. Examples of those core proteins include CSTF2, CPSF1, and subunits of mammalian cleavage factor I. But despite support for these mechanisms, no one has yet documented any of these proteins changing in either a tissue‐specific or developmental manner. Given the profound effect that APA can have on gene expression and human health, improved understanding of tissue‐specific APA could lead to numerous advances in gene activity control. This article is categorized under: RNA Processing > 3′ End Processing RNA in Disease and Development > RNA in Development

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“…This suggests additional cytoplasmic and axonal functions for these RBPs in post-mitotic neurons, perhaps due to the much greater expanses of cytoplasm that neurons must grow and sustain with their long axonal processes. Multifunctionality has been documented for several RBPs, including axonal ZBP1, FMRP, nucleolin, and HuD that contribute to transport and stability or transport and translation of neuronal mRNAs (6,(51)(52)(53)(54). Both the RIP-seq data and depletion studies point to functions in axonal growth for hnRNP H1, F, and K. It will be of high interest to determine the molecular mechanisms for growth promotion by these hnRNPs and distinguish nuclear and somatic vs. axonal functions for these proteins.…”

Section: Sj Lee Et Al Rna-protein Interactions For Axonal Mrnasmentioning

confidence: 99%