Deregulation of neuronal polarization promotes axonal growth after spinal cord injury
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE214722 | GEO | 2024/01/01
REPOSITORIES: GEO
Similar Datasets
Project description:The developmental maturation of a neuron requires the completion of neuronal polarization preceding the formation of a synapse. Whether neuronal polarization marks the decline in growth competence in the injured mammalian adult nervous system remains elusive. Here we show that gene expression and epigenetic signatures associated with the regenerative growth ability of dorsal root ganglia (DRG) sensory neurons are lost during the transition from a non-polarized to a polarized state. The transcriptional co-factor Cited2 was found to be epigenetically upregulated in immature DRG and following a regenerative injury, but it remained unchanged by a non-regenerative spinal cord injury (SCI). Next, Cited2 was overexpressed in DRG neurons in a model of SCI in mice where it promoted sensory axon growth and reversed the gene expression signatures associated with neuronal maturation. Importantly, Cited2 expression stirred the maturation of DRG neurons towards a non-polarized state. Together, these data suggest that the transition from a non-polarized to a polarized state marks the reversible loss of the regenerative ability of a neuron, thus paving the way to targeted repair strategies relying on neuronal de-maturation.
2024-01-01 | GSE224110 | GEO
Project description:Early neuronal development is a well-coordinated process in which neuronal stem cells differentiate into polarized neurons. This process has been well studied in classical non-human model systems, but to what extent this is recapitulated in human neurons remains unclear. To study neuronal polarization in human neurons, we cultured human iPSC-derived neurons, characterized early developmental stages, measured electrophysiological responses, and systematically profiled transcriptomic and proteomic dynamics during these steps. We found extensive remodeling of the neuron transcriptome and proteome, with altered mRNA expression of ~1,100 genes and different expression profiles of ~1,500 proteins during neuronal differentiation and polarization. We also identified a distinct stage in axon development marked by an increase in microtubule remodeling and apparent relocation of the axon initial segment from the distal to proximal axon. Our comprehensive characterization and quantitative map of transcriptome and proteome dynamics provides a solid framework for studying polarization in human neurons.
2020-11-17 | PXD020227 | Pride
Project description:Peripheral nervous system injuries lead to long-term neurological disability due to limited axonal regenerative ability. Injury-dependent and more recently injury-independent physiological mechanisms have provided important molecular insight into regenerative mechanisms. However, whether common molecular denominators underpinning both injury-dependent and independent biological processes exist remains unclear. We initially performed a comparative analysis of recently generated transcriptomic datasets associated with the regenerative ability of sciatic dorsal root ganglia (DRG). Surprisingly, circadian rhythms were identified as a the most significantly enriched biological process associated with regenerative capability. We demonstrate that DRG neurons possess an endogenous circadian clock with a 24h oscillations of circadian genes and that their regenerative ability displays a diurnal oscillation in a mouse model of sciatic nerve injury. Consistently, transcriptomic analysis of DRG neurons showed a significant time-of-day dependent enrichment for processes associated with neuronal development and axonal growth, for regeneration and circadian associated genes, including the core clock genes Bmal1 and Clock. Indeed, DRG-specific ablation of the non-redundant clock gene Bmal1showed that it is required for regenerative gene expression, neuronal intrinsic circadian axonal regeneration and target reinnervation. Lastly, Lithium, a chrono-active compound, enhanced nerve regeneration, in wildtype but not in clock genes Bmal1 and Cry1/2-deficient mice. Together, these data demonstrate that daily rhythms and the circadian clock fine-tune the regenerative response of DRG neurons, and they advocate for the use of chrono-active strategies in time-day dependent modulation of nerve repair.
2024-01-19 | GSE235687 | GEO
Project description:Early neuronal development is a well-coordinated process in which neuronal stem cells differentiate into polarized neurons. This process has been well studied in classical non-human model systems, but to what extent this is recapitulated in human neurons remains unclear. To study neuronal polarization in human neurons, we cultured human iPSC-derived neurons, characterized early developmental stages, measured electrophysiological responses, and systematically profiled transcriptomic and proteomic dynamics during these steps. We found extensive remodeling of the neuron transcriptome and proteome, with altered mRNA expression of ~1,100 genes and different expression profiles of ~1,500 proteins during neuronal differentiation and polarization. We also identified a distinct stage in axon development marked by an increase in microtubule remodeling and apparent relocation of the axon initial segment from the distal to proximal axon. Our comprehensive characterization and quantitative map of transcriptome and proteome dynamics provides a solid framework for studying polarization in human neurons.
2020-07-28 | GSE155212 | GEO
Project description:Transcriptional analysis of identified DRG subpopulations. Cell-type specific intrinsic programs instruct neuronal subpopulations before target-derived factors influence later neuronal maturation. Retrograde neurotrophin signaling controls neuronal survival and maturation of dorsal root ganglion (DRG) sensory neurons, but how these potent signaling pathways intersect with transcriptional programs established at earlier developmental stages remains poorly understood. Here we determine the consequences of genetic alternation of NT3 signaling on genome-wide transcription programs in proprioceptors, an important sensory neuron subpopulation involved in motor reflex behavior. We find that the expression of many proprioceptor-enriched genes is dramatically altered by genetic NT3 elimination, independent of survival-related activities. Combinatorial analysis of gene expression profiles with proprioceptors isolated from mice expressing surplus muscular NT3 identifies an anticorrelated gene set with transcriptional levels scaled in opposite directions. Voluntary running experiments in adult mice further demonstrate the maintenance of transcriptional adjustability of genes expressed by DRG neurons, pointing to life-long gene expression plasticity in sensory neurons. We combined a mouse line expressing GFP under the control of the TrkC promoter (BAC transgene approach) with various NT3 signaling mutants in order to identify the transcriptional changes in identified subpopulations of dorsal root ganglia (DRG) neurons. Sorted cells were processed for RNA extraction and hybridization on Affymetrix microarrays. Analysis was performed a postnatal (p) day p0. Subsequent analysis focused on the transcriptional profile of DRG neuron subpopulations at specific lumbar levels. Additional work addressed the transcriptional changes in whole DRG in adult mice with and without physical exercise.
2012-08-23 | E-GEOD-38074 | biostudies-arrayexpress
Project description:The goal of this study was to compare the transcriptional effects of sciatic nerve injury and spinal cord injury on lumbar dorsal root ganglion (DRG) and FACS-sorted dorsal column (DC) sensory neurons. We performed RNA-seq of whole DRG from naïve and spinal cord-injured (SCI) mice (1dpi) and compared this with previously published data for sciatic nerve transection. In order to assess changes specifically in DC neurons, we performed RNA-seq from FACS-sorted DC neurons from Thy1-YFP16 transgenic mice in naïve, sciatic nerve injured (SNI), and SCI (1 and 3dpi). We found that DC neurons alter their transcriptome after SCI, but that gene changes after SCI mostly differ from SNI. These transcriptional differences may reflect both growth promoting and growth inhibitory effects on axon regeneration after SCI.
2021-01-19 | GSE149646 | GEO
Project description:Transcriptional analysis of identified DRG subpopulations. Cell-type specific intrinsic programs instruct neuronal subpopulations before target-derived factors influence later neuronal maturation. Retrograde neurotrophin signaling controls neuronal survival and maturation of dorsal root ganglion (DRG) sensory neurons, but how these potent signaling pathways intersect with transcriptional programs established at earlier developmental stages remains poorly understood. Here we determine the consequences of genetic alternation of NT3 signaling on genome-wide transcription programs in proprioceptors, an important sensory neuron subpopulation involved in motor reflex behavior. We find that the expression of many proprioceptor-enriched genes is dramatically altered by genetic NT3 elimination, independent of survival-related activities. Combinatorial analysis of gene expression profiles with proprioceptors isolated from mice expressing surplus muscular NT3 identifies an anticorrelated gene set with transcriptional levels scaled in opposite directions. Voluntary running experiments in adult mice further demonstrate the maintenance of transcriptional adjustability of genes expressed by DRG neurons, pointing to life-long gene expression plasticity in sensory neurons.
2012-08-23 | GSE38074 | GEO
Project description:Aggressive inflammation and excessive scar formation are the main cause to the difficulty of neural tissue repair after spinal cord injury (SCI). Microglia and astrocytes act as important role in this micro-environment of SCI and there is cross regulation between microglia and astrocytes. After SCI, MG0 polarized into MG1 and MG3 which were belong to pro-inflammatory phenotype microglia; Naive astrocytes polarized into Reactive and Scar-forming astrocytes. Growth arrest-specific 6 (Gas6) and its receptor Axl was declined in all these cells after SCI. In vitro study, Gas6 had the negative effect on cytotoxic astrocytes and pro-inflammatory microglia polarization and even the cross regulation between cytotoxic astrocytes and pro-inflammatory microglia. Further mechanism study indicated that Gas6 suppressed cytotoxic phenotype polarization of astrocytes through inhibited the activation of YES-associated protein (YAP) signal pathway and suppressed pro-inflammatory phenotype polarization of microglia through inhibited the activation of NF-κB/p65 and JAK/Stat3 signal pathways. In vivo study, Gas6 treatment suppressed cytotoxic astrocytes and pro-inflammatory microglia polarization at the injured site of spinal cord to facilitate tissue repair and loco-motor recovery.
2023-10-21 | GSE245470 | GEO
Project description:Peripheral nerve injury (PNI) could transform primary somatosensory neurons into regenerative state. However, details of transcriptomic changes associated to nerve regeneration of somatosensory neurons maintain unclear. 10x single-cell RNA sequencing (scRNA-seq) was conducted on mice dorsal root ganglia (DRG) cells after early stage of nerve injury on day 3 post-constriction chronic injury (CCI). We observed that a novel CCI-induced neuronal population (CIP) emerged and expressed high levels of activating transcription factor (Atf3), a neuronal injury marker. CIP neurons highly expressed regenerative associated genes (RAGs) and were enriched in regeneration-related gene ontology (GO) terms, suggesting these neurons could be a pro-regenerative population. Moreover, intercellular communication networks showed that CIP neurons have a close communication to satellite glia cells (SGCs) and specifically transmitted strong Fgf3-Fgfr1 signaling to SGCs, which could initiate regeneration-associated transcriptional changes of SGCs. This study also confirmed that the regenerative progress occurred at the early stage of nerve injury because immunohistochemistry showed the expression of ATF3 significantly increased since day 3 post-CCI and decreased at 1 month. Our bioinformatics analysis at single-cell resolution advances the knowledge of regenerative dynamic transcriptional changes of DRG cells after injuries and their underlying molecular mechanisms.
2024-02-09 | GSE255014 | GEO
Project description:Unbiased 'omics' techniques, such as next generation RNA-sequencing, can provide entirely novel insights into biological systems. However, cellular heterogeneity presents a significant barrier to analysis and interpretation of these datasets. The neurons of the dorsal root ganglia (DRG) are an important model for studies of neuronal injury, regeneration and pain. The majority of investigators utilize a dissociated preparation of whole ganglia when studying cellular and molecular function. We demonstrate that the standard methods for producing these preparations gives a 10%-neuronal mixture of cells, with the remainder of cells constituting satellite glia and other non-neuronal cell types. Using a novel application of magnetic purification, we consistently obtain over 95% pure, viable neurons from adult tissue, significantly enriched for small diameter nociceptors expressing the voltage gated ion channel Nav1.8. Using genome-wide RNA-sequencing we compare the currently used (10% neuronal) and pure (95% nociceptor) preparations and find 920 genes enriched. This gives an unprecedented insight into the molecular composition of small nociceptive neurons in the DRG, potentially altering the interpretation of previous studies performed at the tissue level, and indicating a number of novel markers of this widely-studied population of cells. We anticipate that the ease of use, affordability and speed of this technique will see it become widely adopted, delivering a greatly improved capacity to study the roles of nociceptors in health and disease. RNA-Seq was performed for 4 biological replicates from three different groups: intact DRG, acutely dissociated DRG and magnetically-purified DRG neurons. Differential expression was analyzed between acutely dissociated and MACS-dissociated samples to define the 'nociceptor transcriptome'.
2014-11-17 | E-GEOD-62424 | biostudies-arrayexpress