DLK regulates a distinctive transcriptional regeneration program after peripheral nerve injury.
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ABSTRACT:
SUBMITTER: Shin JE
PROVIDER: S-EPMC6588443 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
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Project description:Robust axon regeneration of motoneurons (MNs) occurs in rodent models upon peripheral nerve injury (PNI). However, genome-wide dynamic molecules and permissive microenvironment following insult in MNs remain largely unknown. Here, we firstly tackled by high-coverage and massive sequencing of laser-dissected individual ChAT+ cells to uncover molecules and pro-regenerative programs of MNs from injury to the regenerating phase after PNI. "Injured" populations at 1d∼7d were well distinguished and three response phases were well defined by elucidating with several clues (Gap43, etc). We found remarkable changes of genes expressed by injured motoneurons to activate and enhance intrinsic axon regrowth or crosstalk with other cellular or non-cellular counterpart in the activated regenerative microenvironment, specifically microglia/macrophage. We also identified an injury and regeneration-associated module and critical regulators including core transcription factors (Atf3, Arid5a, Klf6, Klf7, Jun, Stat3, and Myc). This study provides a vital resource and critical molecules for studying neural repair of axotomized motoneurons.
| S-EPMC9424597 | biostudies-literature
Project description:Axon injury triggers regeneration through activation of a conserved kinase cascade, which includes the dual leucine zipper kinase (DLK). Although dendrites are damaged during stroke, traumatic brain injury, and seizure, it is not known whether mature neurons monitor dendrite injury and initiate regeneration. We probed the response to dendrite damage using model Drosophila neurons. Two larval neuron types regrew dendrites in distinct ways after all dendrites were removed. Dendrite regeneration was also triggered by injury in adults. Next, we tested whether dendrite injury was initiated with the same machinery as axon injury. Surprisingly, DLK, JNK, and fos were dispensable for dendrite regeneration. Moreover, this MAP kinase pathway was not activated by injury to dendrites. Thus, neurons respond to dendrite damage and initiate regeneration without using the conserved DLK cascade that triggers axon regeneration.
| S-EPMC3954604 | biostudies-literature
Project description:BackgroundClearance of myelin debris and remyelination of myelin are necessary steps for peripheral nerve remodeling and regeneration. It has yet to be clarified which genes or proteins are involved in endocytosis or exocytosis in the removal of myelin debris during peripheral nerve repair.MethodsFor this project, a rat model of subacute stage of sciatic nerve injury was established first. Subsequently, normal Schwann cells (NSCs) and activated Schwann cells (ASCs) were harvest before and after peripheral nerve injury (PNI). Following methylated DNA immunoprecipitation sequencing (MeDIP-seq) and tandem mass tags (TMT) labeling analysis of NSCs and ASCs, what common biomarkers changes in peripheral nervous systems remain to be elucidated.ResultsA total of 14,770 different expression genes (DEGs) and 3249 different expression proteins (DEPs) were screened between ASCs and NSCs. For the exosomes, the diameter and particles concentration of exosomes were 141.7 nm and 2.97 × 107 particles/mL, respectively. The size distribution of exosomes was 50-200 nm. ASCs showed higher cellular uptake ability than the NSCs by cellular uptake test. Moreover, RAB7A, ARF6, ARF1, VPS45, RAB11A, DNM3, and NEDD4 were the core markers and may control the molecular mechanism of the Endocytosis pathway.ConclusionThese biomarkers may play significant roles in the initiation phase of demyelination and axon regeneration.The translational potential of this articleThis study explores that the endocytosis-associated patterns of Schwann cells may be new therapeutic strategy for nerve tissue engineering and nerve regeneration.
| S-EPMC8551787 | biostudies-literature
Project description:The effect of platelet-rich plasma on nerve regeneration remains controversial. In this study, we established a rabbit model of sciatic nerve small-gap defects with preserved epineurium and then filled the gaps with platelet-rich plasma. Twenty-eight rabbits were divided into the following groups (7 rabbits/group): model, low-concentration PRP (2.5-3.5-fold concentration of whole blood platelets), medium-concentration PRP (4.5-6.5-fold concentration of whole blood platelets), and high-concentration PRP (7.5-8.5-fold concentration of whole blood platelets). Electrophysiological and histomorphometrical assessments and proteomics analysis were used to evaluate regeneration of the sciatic nerve. Our results showed that platelet-rich plasma containing 4.5-6.5- and 7.5-8.5-fold concentrations of whole blood platelets promoted repair of sciatic nerve injury. Proteomics analysis was performed to investigate the possible mechanism by which platelet-rich plasma promoted nerve regeneration. Proteomics analysis showed that after sciatic nerve injury, platelet-rich plasma increased the expression of integrin subunit β-8 (ITGB8), which participates in angiogenesis, and differentially expressed proteins were mainly enriched in focal adhesion pathways. Additionally, two key proteins, ribosomal protein S27a (RSP27a) and ubiquilin 1 (UBQLN1), which were selected after protein-protein interaction analysis, are involved in the regulation of ubiquitin levels in vivo. These data suggest that platelet-rich plasma promotes peripheral nerve regeneration after sciatic nerve injury by affecting angiogenesis and intracellular ubiquitin levels.
| S-EPMC9396478 | biostudies-literature
Project description:Expression of whole retina after optic nerve crush. The "SAMPLE_ID" sample characteristic is a sample identifier internal to Genentech. The ID of this project in Genentech's ExpressionPlot database is PRJ0004847
2017-03-16 | GSE96053 | GEO
Project description:Accumulating evidence suggests that circular RNAs (circRNAs) are abundant and play critical roles in the nervous system. However, their functions in axon regeneration after neuronal injury are unclear. Due to its robust regeneration capacity, peripheral nervous system is ideal for seeking the regulatory circRNAs in axon regeneration. In the present work, we obtained an expression profile of circRNAs in dorsal root ganglions (DRGs) after rat sciatic nerve crush injury by RNA sequencing (RNA-Seq) and found the expression level of circ-Spidr was obviously increased using quantitative real-time polymerase chain reaction (qRT-PCR). Furthermore, circ-Spidr was proved to be a circular RNA enriched in the cytoplasm of DRG neurons. Through in vitro and in vivo experiments, we determined that down-regulation of circ-Spidr could suppress axon regeneration of DRG neurons after sciatic nerve injury partially through modulating PI3K-Akt signaling pathway. Together, our results reveal a crucial role for circRNAs in regulating axon regeneration after neuronal injury which may further serve as a potential therapeutic avenue for neuronal injury repair.
| S-EPMC6797756 | biostudies-literature
Project description:Traumatic insults to the spinal cord induce both immediate mechanical damage and subsequent tissue degeneration leading to a substantial physiological, biochemical, and functional reorganization of the spinal cord. Various spinal cord injury (SCI) models have shown the adaptive potential of the spinal cord and its limitations in the case of total or partial absence of supraspinal influence. Meaningful recovery of function after SCI will most likely result from a combination of therapeutic strategies, including neural tissue transplants, exogenous neurotrophic factors, elimination of inhibitory molecules, functional sensorimotor training, and/or electrical stimulation of paralyzed muscles or spinal circuits. Peripheral nerve grafts provide a growth-permissive substratum and local neurotrophic factors to enhance the regenerative effort of axotomized neurons when grafted into the site of injury. Regenerating axons can be directed via the peripheral nerve graft toward an appropriate target, but they fail to extend beyond the distal graft-host interface because of the deposition of growth inhibitors at the site of SCI. One method to facilitate the emergence of axons from a graft into the spinal cord is to digest the chondroitin sulfate proteoglycans that are associated with a glial scar. Importantly, regenerating axons that do exit the graft are capable of forming functional synaptic contacts. These results have been demonstrated in acute injury models in rats and cats and after a chronic injury in rats and have important implications for our continuing efforts to promote structural and functional repair after SCI.
| S-EPMC3101823 | biostudies-other
Project description:The cell intrinsic factors that determine whether a neuron regenerates or undergoes apoptosis in response to axonal injury are not well defined. Here we show that the mixed-lineage dual leucine zipper kinase (DLK) is an essential upstream mediator of both of these divergent outcomes in the same cell type. Optic nerve crush injury leads to rapid elevation of DLK protein, first in the axons of retinal ganglion cells (RGCs) and then in their cell bodies. DLK is required for the majority of gene expression changes in RGCs initiated by injury, including induction of both proapoptotic and regeneration-associated genes. Deletion of DLK in retina results in robust and sustained protection of RGCs from degeneration after optic nerve injury. Despite this improved survival, the number of axons that regrow beyond the injury site is substantially reduced, even when the tumor suppressor phosphatase and tensin homolog (PTEN) is deleted to enhance intrinsic growth potential. These findings demonstrate that these seemingly contradictory responses to injury are mechanistically coupled through a DLK-based damage detection mechanism.
| S-EPMC3593899 | biostudies-other
Project description:Severe peripheral nerve injuries often result in partial repair and lifelong disabilities in patients. New surgical techniques and better graft tissues are being studied to accelerate regeneration and improve functional recovery. Currently, limited tools are available to provide in vivo monitoring of changes in nerve physiology such as myelination and vascularization, and this has impeded the development of new therapeutic options. We have developed a wide-field and label-free functional microscopy platform based on angiographic and vectorial birefringence methods in optical coherence tomography (OCT). By incorporating the directionality of the birefringence, which was neglected in the previously reported polarization-sensitive OCT techniques for nerve imaging, vectorial birefringence contrast reveals internal nerve microanatomy and allows for quantification of local myelination with superior sensitivity. Advanced OCT angiography is applied in parallel to image the three-dimensional vascular networks within the nerve over wide-fields. Furthermore, by combining vectorial birefringence and angiography, intraneural vessels can be discriminated from those of the surrounding tissues. The technique is used to provide longitudinal imaging of myelination and revascularization in the rodent sciatic nerve model, i.e. imaged at certain sequential time-points during regeneration. The animals were exposed to either crush or transection injuries, and in the case of transection, were repaired using an autologous nerve graft or acellular nerve allograft. Such label-free functional imaging by the platform can provide new insights into the mechanisms that limit regeneration and functional recovery, and may ultimately provide intraoperative assessment in human subjects.
| S-EPMC6143548 | biostudies-literature
Project description:Observing the structure and regeneration of the myelin sheath in peripheral nerves following injury and during repair would help in understanding the pathogenesis and treatment of neurological diseases caused by an abnormal myelin sheath. In the present study, transmission electron microscopy, immunofluorescence staining, and transcriptome analyses were used to investigate the structure and regeneration of the myelin sheath after end-to-end anastomosis, autologous nerve transplantation, and nerve tube transplantation in a rat model of sciatic nerve injury, with normal optic nerve, oculomotor nerve, sciatic nerve, and Schwann cells used as controls. The results suggested that the double-bilayer was the structural unit that constituted the myelin sheath. The major feature during regeneration was the compaction of the myelin sheath, wherein the distance between the 2 layers of cell membrane in the double-bilayer became shorter and the adjacent double-bilayers tightly closed together and formed the major dense line. The expression level of myelin basic protein was positively correlated with the formation of the major dense line, and the compacted myelin sheath could not be formed without the anchoring of the lipophilin particles to the myelin sheath.
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