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Signaling to Transcription Networks in the Neuronal Retrograde Injury Response

ABSTRACT: Retrograde signaling from axon to soma activates intrinsic regeneration mechanisms in lesioned peripheral sensory neurons; however, the links between axonal injury signaling and the cell body response are not well understood. Here, we used phosphoproteomics and microarrays to implicate ~900 phosphoproteins in retrograde injury signaling in rat sciatic nerve axons in vivo and ~4500 transcripts in the in vivo response to injury in the dorsal root ganglia. Computational analyses of these data sets identified ~400 redundant axonal signaling networks connected to 39 transcription factors implicated in the sensory neuron response to axonal injury. Experimental perturbation of individual overrepresented signaling hub proteins, including Abl, AKT, p38, and protein kinase C, affected neurite outgrowth in sensory neurons. Paradoxically, however, combined perturbation of Abl together with other hub proteins had a reduced effect relative to perturbation of individual proteins. Our data indicate that nerve injury responses are controlled by multiple regulatory components, and suggest that network redundancies provide robustness to the injury response

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE26350 | GEO | 2010/12/29

SECONDARY ACCESSION(S): PRJNA136731

REPOSITORIES: GEO

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Signaling to Transcription Networks in the Neuronal Retrograde Injury Response

Project description:Retrograde signaling from axon to soma activates intrinsic regeneration mechanisms in lesioned peripheral sensory neurons; however, the links between axonal injury signaling and the cell body response are not well understood. Here, we used phosphoproteomics and microarrays to implicate ~900 phosphoproteins in retrograde injury signaling in rat sciatic nerve axons in vivo and ~4500 transcripts in the in vivo response to injury in the dorsal root ganglia. Computational analyses of these data sets identified ~400 redundant axonal signaling networks connected to 39 transcription factors implicated in the sensory neuron response to axonal injury. Experimental perturbation of individual overrepresented signaling hub proteins, including Abl, AKT, p38, and protein kinase C, affected neurite outgrowth in sensory neurons. Paradoxically, however, combined perturbation of Abl together with other hub proteins had a reduced effect relative to perturbation of individual proteins. Our data indicate that nerve injury responses are controlled by multiple regulatory components, and suggest that network redundancies provide robustness to the injury response Microarrays were run on mRNA extracted from adult rat L4 and L5 DRGs cells after 1,3,8,12,16,18,24, and 28 hours after a sciatic nerve (proximal and distal) lesion.

2010-12-29 | E-GEOD-26350 | biostudies-arrayexpress

DOK6 Selectively Docks the Neurotrophic Signaling Transduction to Restrain Peripheral Neuropathy

Project description:The appropriate and specific response of nerve cells to various external cues is essential for the establishment and maintenance of neural circuits, and this process requires the proper recruitment of adaptor molecules to selectively activate downstream pathways. Here, we identified that DOK6 is required for the maintenance of peripheral axons, and loss of Dok6 can cause typical peripheral neuropathy symptoms in mice, manifested as impaired sensory, abnormal posture, paws deformities, blocked nerve conduction, and dysmyelination. Furthermore, genetic deletion of Dok6 in peripheral neurons led to axonal degeneration and hindered retrograde axonal transport. Specifically, DOK6 acts as an adaptor protein for selectivity-mediated neurotrophic signal transduction and retrograde transport for TrkC and Ret but not TrkA and TrkB. DOK6 interacts with certain proteins in the trafficking machinery and controls their phosphorylation, including MAP1B, Tau and Dynein for axonal transport, and specifically activates the downstream ERK1/2 kinase pathway to maintain axonal survival and homeostasis. This finding provides new clues to potential insights into the pathogenesis and treatment of hereditary peripheral neuropathies or other degenerative diseases.

2024-02-02 | GSE249502 | GEO

Transcriptional reprogramming of distinct peripheral sensory neuron subtypes after axonal injury

Project description:Primary somatosensory neurons specialize in transmitting distinct types of sensory information through differences in cell size, myelination, and the expression of various receptors and ion channels, which together define their transcriptional and functional identity. By profiling sensory ganglia at single-cell resolution, we find that the different somatosensory neuronal subtypes undergo a similar transcriptional response to peripheral nerve injury that both promotes axonal regeneration and suppresses cell identity. This transcriptional reprogramming, which is not observed in non-neuronal cells from sensory ganglia, resolves over a similar time course as target reinnervation and is associated with the restoration of original cell identity. Injury-induced transcriptional reprogramming requires ATF3, a transcription factor which is induced rapidly after injury and necessary for axonal regeneration and functional recovery. Our findings suggest that the transcription factors induced early after peripheral sensory neuron injury promote their transcriptional and functional metamorphosis, analogous to their known roles in reprogramming cell fate.

2020-07-22 | GSE154659 | GEO

Transcription profiling of mouse optic nerves as a model for axonal injury

Project description:We used optic nerve injury as a model to study early signaling events in the neuronal soma following axonal injury. Optic nerve injury results in the selective death of retinal ganglion cells (RGCs). The time course of cell death takes place over a period of days with the earliest detection of RGC death at about 48 hr post injury. We hypothesized that in the period immediately following axonal injury, there are changes in the soma that signal surrounding glia and neurons and that start programmed cell death. In the current study, we investigated early changes in cellular signaling and gene expression that occur within the first 6 hrs post optic nerve injury. We detected differences in phosphoproteins and gene expression within this time period that we used to interpret temporal events. Our studies revealed that the entire retina has been signaled by the RGC soma within 30 min after optic nerve injury and that pathways that modulate cell death are likely to be active in RGCs within 6 hrs following axonal injury Experiment Overall Design: In the treated animals, axons of the optic nerve were crushed with fine forceps for 10 sec, 1 mm posterior to the globe, under direct visualization, within an intact meningeal sheath. Controls were contralateral eyes from the same animals in each group that had not been injured. After 6 hr eyes were enucleated and processed for tissue sectionin

2008-10-25 | E-GEOD-11862 | biostudies-arrayexpress

Early Gene expression changes after axonal injury

2008-09-01 | GSE11862 | GEO

Sensory neurons display cell-type specific vulnerability to loss of neuron-glia interactions

Project description:PNS injuries initiate transcriptional changes in glial cells and sensory neurons that promote axonal regeneration. While the factors that initiate the transcriptional changes in glial cells are well characterized, the full range of stimuli that initiate the response of sensory neurons remain elusive. Here, using a genetic model of glial cell ablation, we find that glial cell loss results in transient PNS demyelination without overt axonal loss. By profiling sensory ganglia at single-cell resolution we show that glial cell loss induces a transcriptional injury response preferentially in proprioceptive and Aβ RA-LTMR neurons. The transcriptional response of sensory neurons to mechanical injury has been assumed to be a cell autonomous response. By identifying a similar response in non-injured, demyelinated neurons, our study suggests that this represents a non-cell autonomous transcriptional response of sensory neurons to the loss of axon-glial cell interactions.

2022-06-11 | GSE205561 | GEO

Timecourse expression data from sciatic nerve distal stump of C57BL/6 and C57BL/6 OlaHsd-Wlds mice.

Project description:Wallerian degeneration (WD) involves the fragmentation of axonal segments disconnected from their cell bodies, segmentation of the myelin sheath, and removal of debris by Schwann cells and immune cells. The removal and downregulation of myelin-associated inhibitors of axonal regeneration and synthesis of growth factors by these two cell types are critical responses to successful nerve repair. Here, we analyzed the transcriptome of the sciatic nerve of mice carrying the Wallerian degeneration slow (WldS) mutant gene, a gene that confers axonal protection in the distal stump after injury, therefore causing significant delays in WD, neuroinflammation, and axonal regeneration. 56 C57BL6 mice and 56 C57BL/6 OlaHsd-Wlds mice were anesthetized with isoflurane and underwent a microcrush lesion of their left sciatic nerve at the mid-thigh level (exept naive mice, t0). At 0, 3, 7 and 14 days post-injury, mice were anesthetized and killed by cervical dislocation. Sciatic nerves were collected and conective tissue removed. A 4-mm long sciatic nerve segment was taken from the nerve distal stump, starting at 1 mm distal from the lesion up to 5 mm distal. Distal nerve stumps were pooled by group and RNA extracted. Samples were hybridized to GeneChip® Mouse Genome 430 2.0 Array (Affymetrix). Biological replicate was done.

2011-06-01 | E-GEOD-22291 | biostudies-arrayexpress

RNA sequencing of Dorsal Root Ganglia upon axonal injury, in presence or absence of NAC (N-acetyl cysteine), and upon H2O2 nerve treatment

Project description:Purpose: A) compare the response to an axonal injury in the peripheral vs central nervous system B) clarify the mechanism of Reactive Oxygen Species-dependent axonal regeneration Results: we found that after peripheral axonal injury there is a higher number of differentially expressed genes with respect to central injury. Moreover,inflammation related genes and regeneration-associated genes were differentially regulated after peripheral injury and H2O2, but less after central injury. Signalling pathways and biological processes related to injury-dependent nerve regeneration were reduced with the addition of NAC at the time of sciatic injury compared to vehicle.

2018-07-06 | GSE97090 | GEO

Differential gene expression analysis in motor and sensory cortex as a result of experimental autoimmune encephalomyelitis (EAE), a neuroinflammatory model for Multiple sclerosis.

Project description:We performed micrarrays to investigate neuronal gene expression changes during acute inflammatory CNS axon injury using the murine myelin oligodendrocyte glycoprotein 35-55 (MOG35-55)-induced experimental autoimmune encephalomyelitis (EAE) model. The present study was assigned to assess the direct and indirect endogenous neuronal response to spinal axonal injury in the motor and sensory cortex. Gene expression in motor and sensory cortex enriched tissue was assessed from four healthy and six EAE female mice. Tissue was collected from mice with paraplegia or monoplegia, with contralateral hindlimb paresis (EAE day 18-21). The gene expression profiles of the EAE mice were compared to the motor or sensory cortex of healthy control mice, resulting in a list of differentially expressed genes in healthy and EAE mice.

2014-10-01 | E-GEOD-47900 | biostudies-arrayexpress

Rat motor and sensory nerve LC-MSMS

Project description:Peripheral nerve repair and functional recovery depend on the rate of nerve regeneration and the quality of target reinnervation. It is important to fully understand the cellular and molecular basis underlying the specificity of peripheral nerve regeneration, which means the achieving of respective correct pathfinding and accurate target reinnervation for regrowing motor and sensory axons. In this study, a quantitative proteomic technique, based on isobaric tags for relative and absolute quantitation (iTRAQ) was used to profile the protein expression pattern between single motor and sensory nerves at 14 days after peripheral nerve transection. Among a total of 1259 proteins identified, 176 proteins showed the differential expressions between injured motor and sensory nerves. Quantitative real-time RT-PCR and Western blot analysis were applied to validate the proteomic data on representative differentially expressed proteins. Functional categorization indicated that differentially expressed proteins were linked to a diverse array of molecular functions, including axonogenesis, response to axon injury, tissue remodeling, axon ensheathment, cell proliferation and adhesion, vesicle-mediated transport, response to oxidative stress, internal signal cascade, and macromolecular complex assembly, which might play an essential role in peripheral motor and sensory nerve regeneration. Overall, we hope that the proteomic database obtained in this study could serve as a solid foundation for the comprehensive investigation of differentially expressed proteins between injured motor and sensory nerves and for the mechanism elucidation of the specificity of peripheral nerve regeneration.

2020-12-10 | PXD022097 | Pride

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