Price, T. | bioRxiv Science

bioRxiv2018

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

Pain sensing neurons, nociceptors, are key drivers of neuropathic pain. We used translating ribosome affinity purification (TRAP) to comprehensively characterize up-and down-regulated mRNA translation in Scn10a-positive nociceptors in chemotherapy-induced neuropathic pain. We provide evidence that an underlying mechanism driving these changes in gene expression is a sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, a GTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling, demonstrating a new link between these distinct signaling pathways. Neuropathic pain and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We reveal a novel translational circuit for the genesis of neuropathic pain with important implications for next generation neuropathic pain therapeutics.\n\nOne Sentence SummaryCell-specific sequencing of translating mRNAs elucidates signaling pathology that can be targeted to reverse neuropathic pain

neuroscience↗

bioRxiv2018

Strong hybrid male incompatibilities impede the spread of a selfish chromosome between populations of a fly.

Meiotically driving sex chromosomes manipulate gametogenesis to increase their transmission at a cost to the rest of the genome. The intragenomic conflicts they produce have major impacts on the ecology and evolution of their host species. However their ecological dynamics remain poorly understood. Simple population genetic models predict meiotic drivers will rapidly reach fixation in a population and spread across a landscape. In contrast, natural populations commonly show spatial variation in the frequency of drivers, with drive present in clines or mosaics across species ranges. For example, Drosophila subobscura harbours a Sex Ratio distorting drive chromosome (\"SRs\") at 15-25% frequency in North Africa, present at less than 2% frequency in adjacent Southern Spain and absent in other European populations. Here, we investigate the forces preventing the spread of the driver northward. We show that SRs has remained at a constant frequency in North Africa, and failed to spread in Spain. We find strong evidence in favour of our first hypothesis, genetic incompatibility between SRs and Spanish autosomal background. When we cross SRs from North Africa onto Spanish genetic backgrounds we observe strong SRs specific incompatibilities in hybrids. The incompatibilities increase in severity in F2 male hybrids, leading to almost complete infertility. We find no evidence supporting a second hypothesis, that there is resistance to drive in Spanish populations. We conclude that the source of the stepped frequency variation is genetic incompatibility between the SRs chromosome and the genetic backgrounds of the adjacent population, preventing SRs spreading northward. The low frequency of SRs in South Spain is consistent with recurrent gene flow across the Strait of Gibraltar combined with selection against the SRs element through genetic incompatibility. This demonstrates that incompatibilities between drive chromosomes and naive populations can prevent the spread of drive between populations, at a continental scale.

evolutionary biology↗