Nociceptor translational profiling reveals the RagA-mTORC1 network as a critical generator of neuropathic pain

Megat, Salim; Ray, Pradipta; Moy, Jamie K.; Lou, Tzu-Fang; Barragán-Iglesias, Paulino; Li, Yan; Pradhan, Grishma; Wangzhou, Andi; Ahmad, Ayesha; North, Robert Y.; Dougherty, Patrick M.; Khoutorsky, Arkady; Sonenberg, Nahum; Webster, Kevin R.; Dussor, Gregory; Campbell, Zachary T.; Price, Theodore J.

doi:10.1101/336784

Cited by 2 publications

(6 citation statements)

References 34 publications

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“…7-2, available at https://doi.org/10.1523/JNEUROSCI. 2663-18.2019.f7-2), a finding that is consistent with observations in DRG Nav1.8-expressing neurons (Megat et al, 2019).…”

Section: Nav1supporting

confidence: 90%

“…This approach generates Nav1.8-TRAP neurons in both the DRG and TG. While the specificity of our approach was recently shown in the DRG (Megat et al, 2019), we characterized expression of the transgene in the TG (Fig. 1A).…”

Section: Resultsmentioning

confidence: 96%

“…Here, we also detected a higher level of eIF4E phosphorylation in the TG compared with DRG ( Fig. 6D), suggesting that TG nociceptors may display higher translational activity via this pathway than their DRG counterparts (Megat et al, 2019). We also focused on Akt1s1, which encodes the PRAS40 protein, because this is a negative regulator of mTORC1 activity with actions that are inversely related to RagA (Wiza et al, 2012;Chong, 2016).…”

Section: Nav1mentioning

confidence: 81%

“…To make comparisons between the TG and DRG, we generated TRAP sequencing from the TG that was then compared with our previously generated DRG dataset (GSE 113941). We sequenced the total mRNA input from all biological replicates and mRNAs associated with translating ribosomes in the Nav1.8 subset of TG neurons, equivalently to what was done from DRG (Megat et al, 2019). This approach allowed us to make comparisons between the whole tissue transcriptional and Nav1.8 ϩ neuron translational landscapes between DRG and TG.…”

Section: Resultsmentioning

confidence: 99%

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Differences between Dorsal Root and Trigeminal Ganglion Nociceptors in Mice Revealed by Translational Profiling

Megat¹,

Ray²,

Tavares‐Ferreira³

et al. 2019

J. Neurosci.

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Nociceptors located in the trigeminal ganglion (TG) and DRG are the primary sensors of damaging or potentially damaging stimuli for the head and body, respectively, and are key drivers of chronic pain states. While nociceptors in these two tissues show a high degree of functional similarity, there are important differences in their development lineages, their functional connections to the CNS, and recent genome-wide analyses of gene expression suggest that they possess some unique genomic signatures. Here, we used translating ribosome affinity purification to comprehensively characterize and compare mRNA translation in Scn10a-positive nociceptors in the TG and DRG of male and female mice. This unbiased method independently confirms several findings of differences between TG and DRG nociceptors described in the literature but also suggests preferential utilization of key signaling pathways. Most prominently, we provide evidence that translational efficiency in mechanistic target of rapamycin (mTOR)-related genes is higher in the TG compared with DRG, whereas several genes associated with the negative regulator of mTOR, AMP-activated protein kinase, have higher translational efficiency in DRG nociceptors. Using capsaicin as a sensitizing stimulus, we show that behavioral responses are greater in the TG region and this effect is completely reversible with mTOR inhibition. These findings have implications for the relative capacity of these nociceptors to be sensitized upon injury. Together, our data provide a comprehensive, comparative view of transcriptome and translatome activity in TG and DRG nociceptors that enhances our understanding of nociceptor biology.

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“…7-2, available at https://doi.org/10.1523/JNEUROSCI. 2663-18.2019.f7-2), a finding that is consistent with observations in DRG Nav1.8-expressing neurons (Megat et al, 2019).…”

Section: Nav1supporting

confidence: 90%

Section: Resultsmentioning

confidence: 96%

Section: Nav1mentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

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Differences between Dorsal Root and Trigeminal Ganglion Nociceptors in Mice Revealed by Translational Profiling

Megat¹,

Ray²,

Tavares‐Ferreira³

et al. 2019

J. Neurosci.

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“…BDNF is a key molecule mediating pain plasticity ( Obata and Noguchi, 2006 ) and identification of MNK/eIF4E signaling as a central regulator of Bdnf translation has important therapeutic implications ( Moy et al, 2018a ). Cell-type specific translational profiling of nociceptors [using translating ribosome affinity purification (TRAP) approach] ( Heiman et al, 2014 ) in a mouse model of chemotherapy-induced neuropathic pain revealed that MNK-eIF4E signaling controls translation of RagA mRNA, a key regulator of mTORC1 ( Megat et al, 2018 ). This finding suggests crosstalk between ERK/MNK/eIF4E and mTORC1 signaling pathways in promoting pain hypersensitivity in chemotherapy-induced neuropathies.…”

Section: Eif4e In Regulation Of Peripheral Nociceptive Plasticitymentioning

confidence: 99%

eIF4E-Dependent Translational Control: A Central Mechanism for Regulation of Pain Plasticity

et al. 2018

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Translational control of gene expression has emerged as a key mechanism in regulating different forms of long-lasting neuronal plasticity. Maladaptive plastic reorganization of peripheral and spinal nociceptive circuits underlies many chronic pain states and relies on new gene expression. Accordingly, downregulation of mRNA translation in primary afferents and spinal dorsal horn neurons inhibits tissue injury-induced sensitization of nociceptive pathways, supporting a central role for translation dysregulation in the development of persistent pain. Translation is primarily regulated at the initiation stage via the coordinated activity of translation initiation factors. The mRNA cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E), is involved in the recruitment of the ribosome to the mRNA cap structure, playing a central role in the regulation of translation initiation. eIF4E integrates inputs from the mTOR and ERK signaling pathways, both of which are activated in numerous painful conditions to regulate the translation of a subset of mRNAs. Many of these mRNAs are involved in the control of cell growth, proliferation, and neuroplasticity. However, the full repertoire of eIF4E-dependent mRNAs in the nervous system and their translation regulatory mechanisms remain largely unknown. In this review, we summarize the current evidence for the role of eIF4E-dependent translational control in the sensitization of pain circuits and present pharmacological approaches to target these mechanisms. Understanding eIF4E-dependent translational control mechanisms and their roles in aberrant plasticity of nociceptive circuits might reveal novel therapeutic targets to treat persistent pain states.

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Nociceptor translational profiling reveals the RagA-mTORC1 network as a critical generator of neuropathic pain

Cited by 2 publications

References 34 publications

Differences between Dorsal Root and Trigeminal Ganglion Nociceptors in Mice Revealed by Translational Profiling

Differences between Dorsal Root and Trigeminal Ganglion Nociceptors in Mice Revealed by Translational Profiling

eIF4E-Dependent Translational Control: A Central Mechanism for Regulation of Pain Plasticity

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