Abstract
Regeneration failure after spinal cord injury (SCI) results in part from the lack of a pro-regenerative response in injured neurons, but the response to SCI has not been examined specifically in injured sensory neurons. Using RNA sequencing of dorsal root ganglion, we determined that thoracic SCI elicits a transcriptional response distinct from sciatic nerve injury (SNI). Both SNI and SCI induced upregulation of ATF3 and Jun, yet this response failed to promote growth in sensory neurons after SCI. RNA sequencing of purified sensory neurons one and three days after injury revealed that unlike SNI, the SCI response is not sustained. Both SCI and SNI elicited the expression of ATF3 target genes, with very little overlap between conditions. Pathway analysis of differentially expressed ATF3 target genes revealed that fatty acid biosynthesis and terpenoid backbone synthesis were downregulated after SCI but not SNI. Pharmacologic inhibition of fatty acid synthase, the enzyme generating palmitic acid, decreased axon growth and regeneration in vitro. These results support the notion that decreased expression of lipid metabolism-related genes after SCI, including fatty acid synthase, may restrict axon regenerative capacity after SCI.
Highlights
Regeneration failure after spinal cord injury (SCI) results in part from the lack of a pro-regenerative response in injured neurons, but the response to SCI has not been examined in injured sensory neurons
That has transcriptional regulatory roles[13]. These studies suggest that SCI may elicit a transcriptional response in dorsal root ganglion (DRG), but a detailed analysis of how SCI affect gene expression in DRG and sensory neurons has not been performed in detail
We found that SCI elicits a less robust transcriptional response in the DRG compared to sciatic nerve injury (SNI), with fewer differentially expressed (DE) genes compared to SNI (Fig. 1B, Supplementary Tables 1,2)
Summary
Regeneration failure after spinal cord injury (SCI) results in part from the lack of a pro-regenerative response in injured neurons, but the response to SCI has not been examined in injured sensory neurons. In addition to the growth inhibitory environment of the injured spinal cord[1,2], gene profiling studies link regenerative failure after SCI to the lack of an intrinsic transcriptional r esponse[3,4] This is supported by the conditioning injury paradigm, in which prior injury to the peripheral axons of dorsal root ganglion (DRG) sensory neurons promotes axon regeneration of their central axons after SCI5–7. Peripheral nerve injury upregulates many regeneration-associated transcription factors (RATFs)[8,9], yet only modest spinal axon regeneration has been observed by overexpressing R ATFs10–12 This suggests that RATFs expression does not sufficiently recapitulate a growth program and that the intrinsic mechanisms underlying regeneration failure after SCI remains incompletely understood. Part of the transcriptional changes observed after SCI are related to a decrease in lipid metabolism and may repress axon regeneration
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