Transcriptional Reprogramming of Distinct Peripheral Sensory Neuron Subtypes after Axonal Injury

Renthal, William; Tochitsky, Ivan; Yang, Lanbo; Cheng, Yuyu; Li, Emmy; Kawaguchi, Riki; Geschwind, Daniel H.; Woolf, Clifford J.

doi:10.1016/j.neuron.2020.07.026

Cited by 331 publications

(516 citation statements)

References 111 publications

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“…The SNI-induced upregulation of RATFs in ascending sensory neurons was remarkably similar to the response we previously reported in FACS-sorted nociceptors ( Fig S3A-B ) 36 . This is consistent with recent findings indicating that after peripheral nerve injury most sensory neurons adopt a similar transcriptomic state 37 28 . The unique effects of SCI on ascending sensory neurons are thus unlikely related to any intrinsic transcriptional differences between sensory neuron subtypes within the DRG.…”

Section: Resultssupporting

confidence: 93%

“…The upregulation of stress response genes such as ATF3 and Jun suggest that ascending sensory neurons can sense injury after SCI and mount a stress response, but this response is not sufficient to promote a growth state. Our analysis of ATF3 target genes further suggests that in the context of SCI, ATF3 regulates a set of genes that may inhibit ascending sensory neuron growth, whereas in the context of SNI, ATF3 is necessary to transform injured neurons into a regenerative state 28 . We identified downregulation of lipid biosynthesis related genes in ascending sensory neurons after SCI as one possible mechanism that inhibits axon growth.…”

Section: Discussionmentioning

confidence: 82%

“…ATF3 and Jun are required for peripheral nerve regeneration 27 28 . When co-expressed in cultured DRG neurons, ATF3 and Jun promote axon growth in vitro 29 and regeneration of the central axon branch of sensory neurons in vivo 30 .…”

Section: Resultsmentioning

confidence: 99%

“…We next examined ATF3 target genes, because ATF3 is required to induce the transcriptional re-programming of all neuron subtypes after nerve injury, and ATF3 DNA-binding motifs are enriched in the common injury gene set across neuronal subtypes 28 . We identified DE genes that have ATF3 binding sites in the promoter region using Patser software 38 and ATF3 binding matrix obtained from JASPAR database.…”

Section: Resultsmentioning

confidence: 99%

“…Further analysis of the ATF3 target genes in these pathways indicated that most genes were more significantly downregulated after SCI than SNI, and some were upregulated by SNI ( Fig 3H, Supplementary Table 8 ). GO analysis for molecular function of ATF3 target genes further revealed little overlap between SCI and SNI, and also revealed that the downregulation of genes related to ion channel, which is believed to represent in part the loss of neuronal identity after injury 28 , only occurs after SNI ( Fig S4 ). These results reveal that lipid biosynthetic pathways are downregulated in ascending sensory neurons after SCI and may repress axon regeneration.…”

Section: Resultsmentioning

confidence: 99%

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Ascending dorsal column sensory neurons respond to spinal cord injury and downregulate genes related to lipid metabolism

Ewan¹,

Carlin²,

Goncalves³

et al. 2020

Preprint

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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. Analysis of differentially expressed genes revealed that lipid biosynthetic pathways, including fatty acid biosynthesis, were differentially regulated after SCI and SNI. Pharmacologic inhibition of fatty acid synthase, the enzyme generating fatty acid, decreased axon growth in vitro. These findings suggest that decreased fatty acid synthesis inhibits axon regeneration after SCI.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Ascending dorsal column sensory neurons respond to spinal cord injury and downregulate genes related to lipid metabolism

Ewan¹,

Carlin²,

Goncalves³

et al. 2020

Preprint

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An Easy Nanopatch Promotes Peripheral Nerve Repair through Wireless Ultrasound‐Electrical Stimulation in a Band‐Aid‐Like Way

Liu,

Zhang,

Zhao

et al. 2024

Adv Funct Materials

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Low‐intensity pulsed ultrasound (LIPUS) and electrical stimulation (ES) are effective methods that promote neural repair. However, ES usually requires electrode implantation and a power supply, which are an inconvenience to future applications. Meanwhile, it is difficult to combine ultrasound and ES through traditional methods. Herein, a nanopatch consisting of an oriented barium titanate (BTO)‐incorporated polycaprolactone (PCL) nanofiber membrane for electricity generation and a layer of graphene oxide (GO)‐doped gelatin methacryloyl (GelMA) for neural interaction is developed. This band‐aid‐like BTO@PCL/GO@GelMA nanopatch has an excellent piezoelectric performance. In vitro, the nanopatches significantly promote axonal growth under LIPUS treatment. In a rat model of erectile dysfunction caused by peripheral nerve injury, the nanopatch is easily attached to a damaged nerve similar to a band‐aid. With the assistance of ultrasound, some mechanical energy is converted into electricity by the nanopatch, and synergistic neural stimulation of ultrasound and electricity is achieved. In this way, the nanopatch significantly promoted corpus cavernosum nerve repair, resulting in the improvement of tissue structure and erectile function as well as increased conception rate in female rats. In conclusion, the nanopatch offers a synergistic ultrasound‐ES for nerve repair easily and represents a novel strategy for peripheral nerve repair.

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NOCICEPTRA: Gene and microRNA Signatures and Their Trajectories Characterizing Human iPSC‐Derived Nociceptor Maturation

et al. 2021

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Nociceptors are primary afferent neurons serving the reception of acute pain but also the transit into maladaptive pain disorders. Since native human nociceptors are hardly available for mechanistic functional research, and rodent models do not necessarily mirror human pathologies in all aspects, human induced pluripotent stem cell‐derived nociceptors (iDN) offer superior advantages as a human model system. Unbiased mRNA::microRNA co‐sequencing, immunofluorescence staining, and qPCR validations, reveal expression trajectories as well as miRNA target spaces throughout the transition of pluripotent cells into iDNs. mRNA and miRNA candidates emerge as regulatory hubs for neurite outgrowth, synapse development, and ion channel expression. The exploratory data analysis tool NOCICEPTRA is provided as a containerized platform to retrieve experimentally determined expression trajectories, and to query custom gene sets for pathway and disease enrichments. Querying NOCICEPTRA for marker genes of cortical neurogenesis reveals distinct similarities and differences for cortical and peripheral neurons. The platform provides a public domain neuroresource to exploit the entire data sets and explore miRNA and mRNA as hubs regulating human nociceptor differentiation and function.

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Transcriptional Reprogramming of Distinct Peripheral Sensory Neuron Subtypes after Axonal Injury

Cited by 331 publications

References 111 publications

Ascending dorsal column sensory neurons respond to spinal cord injury and downregulate genes related to lipid metabolism

Ascending dorsal column sensory neurons respond to spinal cord injury and downregulate genes related to lipid metabolism

An Easy Nanopatch Promotes Peripheral Nerve Repair through Wireless Ultrasound‐Electrical Stimulation in a Band‐Aid‐Like Way

NOCICEPTRA: Gene and microRNA Signatures and Their Trajectories Characterizing Human iPSC‐Derived Nociceptor Maturation

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