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The oligodendrocyte "protrusiosome": Identification of compartmentalized enrichment of transcripts in newly-formed protrusions of oligodendrocyte precursor cells (OPC) by RNAseq

ABSTRACT: Like neurons, oligodendrocytes (OL) are cells with elaborate morphology that probably require asymmetrical spatial regulation of biological processes. Formation of membrane protrusions is critical for OL development and interaction with axons. We hypothesized that the enrichment of specific mRNAs in protrusions of oligodendrocyte precursor cells (OPC) is important for morphological differentiation, thus having an impact in myelination. To explore this hypothesis, we established a modified Boyden chamber system to physically separate soma from membrane protrusions of rat primary OPC cultured in vitro for 24h. We performed a whole transcriptome analysis (RNAseq) of primary rat OPC soma and membrane protrusion fractions and found a subcellular enrichment of mRNAs in these structures during initial protrusion formation. At the very initial stage of OPC protrusion extension, there is a significant subcellular enrichment of transcripts encoding proteins related to cellular component assembly and cytoskeleton organization, particularly of actin-related molecules. This suggests that the regulation of the cytoskeleton dynamics may be locally controlled in OPCs and probably relevant for their differentiation program.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE106862 | GEO | 2018/05/07

REPOSITORIES: GEO

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The Refilin/Filamin complex regulates filipodia dynamics in oligodendrocyte progenitor cells.

Project description:Actin assembly and dynamics control the shape, motility and functions of diverse cell types. Programme for controlling theses dynamics is hard-coded into actin binding proteins and regulatory proteins. Refilins (RefilinA and RefilinB) are short lived regulatory proteins that interact with the actin-binding protein Filamin to convert it from an actin branching protein into one that bundles. We here show that different mechanisms converge to increase Refilin level in brain NG2+ precursor cells (polydendrocytes) committed to differentiate into the oligodendrocyte lineage. RefilinA is up-regulated through transcriptional activation during commitment into oligodendrocyte progenitor cells (OPC). RefilinB expression relies on PDGF signalling and is further stabilized by a unique auto-inhibitory domain masking the adjacent conserved PEST degradation signal. In NG2+ precursor cells and OPC, the RefilinB/Filamin complex localizes on filipodia protrusions and filipodial processes. Stable ectopic expression of Refilins in cells stimulates membrane remodelling dynamics linked with filipodia growth. These studies extend the function of the Refilin/FLNA complex to cell membrane remodelling linked with reorganization of underlying actin cytoskeleton. We performed whole transcriptomic analysis on the three cell population derived from OPC cells. Three different cultures were done and for each experiment we compared each cell population (NG2+, NG2+/A2B5 and O4) to the other 2 cell populations.

2013-05-01 | E-GEOD-37600 | biostudies-arrayexpress

Molecular maps of the Lamin B1-associated genomic regions in oligodendrocyte lineage cells

Project description:This study addresses the mechanisms regulating the identity of oligodendrocyte progenitor cells (OPC) in physiological conditions and the pathological mechanisms leading to autosomal adrenoleukodystrophy (ADLD), a disease caused by persistence of lamin B1 (LMNB1) expression in oligodendrocytes (OL). Using mouse primary OPCs and a novel technique for the study of DNA-protein interaction, we identify the genomic regions showing dynamic interactions with LMNB1. The transition from ESC to OPC revealed increased association of gene involved in pluripotency and neuronal function and decreased association of gene categories associated with the differentiation of OPC into OL (including genes regulating epigenetic modifiers, RNA processing and protein phosphorylation). Since LMNB1 declines during the transition from OPC to OL, and its persistent expression has been linked to pathological conditions, such as ADLD, we further identified the molecular maps of genome-lamina reorganization in OPC differentiating into OL which continue to express LMNB1 (mOLLMNB1). The transition from OPC to mOLLMNB1 revealed increased association to LMNB1 of genomic regions encoding for lipid metabolism and protein phosphorylation, and decreased association of genes negatively regulating differentiation. These data highlight the importance of LMNB1 in physiological conditions and identify mechanisms responsible for late onset ADLD.

2020-03-16 | GSE135834 | GEO

microRNAs dysregulated in multiple sclerosis affect the differentiation of CG-4 cells, an oligodendrocyte progenitor cell line

Project description:Remyelination in multiple sclerosis (MS) is from the start of the disease imperfect, and strongly decreases with its progression, mainly due to the harm on oligodendrocyte progenitor cells (OPCs), causing neurodegeneration and resulting in irreversible neurological deficits. Therapeutic strategies promoting remyelination are still very preliminary and lack within the current treatment panel of MS. In a previous study we have identified 21 microRNAs dysregulated mostly in the CSF of relapsing and/or remitting MS patients. Here, we observed that among these, the majority of 13 transfected microRNA mimics decreased the differentiation of an OPC cell line called CG-4. Herein we support by RNA sequencing and independent RT-qPCR analyses that miR-33-3p, miR-34c-5p, miR-124-5p, and miR-145-5p impede OPC differentiation as evidenced by the downregulation of premyelinating oligodendrocyte (OL) (Tcf7l2, Cnp [except for miR-145-5p]) and mature OL (Plp1, Mbp, Mobp) markers, whereas only miR-214-3p promotes OPC differentiation. We further propose a comprehensive exploration of their change in cell fate through Gene Ontology enrichment analysis. We finally confirm by RT-qPCR analysis the downregulation of several predicted mRNA targets for each microRNA that possibly support their effect on OPC differentiation by very distinctive mechanisms, of which some are still unexplored in OPC/OL physiology. We hereby open new perspectives in the research on OPC differentiation and the pathophysiology of demyelination/remyelination, and possibly even in the research on new remyelinating therapeutic strategies in the scope of MS.

2024-02-07 | GSE244479 | GEO

Effect of overexpressed UTR constructs on RNA enrichment at protrusions

Project description:We generated fibroblast lines overexpressing beta-globin constructs under a doxycycline-inducible promoter. These constructs contain the beta-globin coding sequence followed by either a control 3'UTR (HBB) or the Pkp4 3'UTR. The Pkp4 3'UTR carries a protrusion-targeting element and is expected to compete with localization of endogenous protrusion-localized mRNAs. We used a fractionation scheme to isolate protrusions and cell bodies from HBB and Pkp4 UTR-expressing fibroblasts, which were induced to extend protrusions in response to addition of lysophosphatidic acid (LPA). 4 replicate protrusion and cell body samples for each cell type were analyzed by RNA-Seq. To identify RNAs enriched in protrusions, a protrusion/cell body ratio was calculated. We find that ca. 4.5% of detected RNAs were enriched in protrusions of control HBB cells. Overexpression of the Pkp4 UTR reduced the protrusion enrichement of a subset of these RNAs, while the degree of localization of the remaining RNAs was not significantly affected.

2017-10-11 | GSE82230 | GEO

The Refilin/Filamin complex regulates filipodia dynamics in oligodendrocyte progenitor cells.

2013-05-01 | GSE37600 | GEO

RNAs enriched at protrusions of control or APC knockdown fibroblasts

Project description:We used a fractionation scheme to isolate protrusions and cell bodies from control or APC knockdown fibroblasts, which were induced to extend protrusions in response to addition of lysophosphatidic acid (LPA). Four replicate protrusion and cell body samples for each cell type were analyzed by RNA-Seq. To identify RNAs enriched in protrusions, a protrusion/cell body ratio was calculated. We find that ca. 7% of detected RNAs were enriched in protrusions of control cells. Knockdown of APC reduced the protrusion enrichement of a subset of these RNAs, indicating that they are dependent on APC for their localization. Localization of the remaining RNAs was not significantly affected upon APC knockdown suggesting that their localization is mediated by an APC-independent mechanism.

2017-10-11 | GSE82229 | GEO

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

Project description:Characterizing the developmental trajectory of oligodendrocyte progenitor cells (OPC) is of great interest given the importance of these cells in the remyelination process. However, studiescof human OPC development remain limited by the availability of whole cell samples and material that encompasses a wide age range, including time of peak myelination. In this study, we apply single cell RNA sequencing to viable whole cells across the age span and link transcriptomic signatures of oligodendrocyte-lineage cells with stage-specific functional properties. Cells were isolated from surgical tissue samples of second-trimester fetal, 2 year old pediatric, 13 year old adolescent, and adult donors by mechanical and enzymatic digestion, followed by percoll gradient centrifugation. Gene expression was analyzed using droplet-based RNA sequencing (10X Chromium). Louvain clustering analysis identified 3 distinct cellular subpopulations based on 5613 genes, comprised of an early OL precursor cell (e-OPC) group, a late OPC group (l-OPC), and a mature OL (MOL) group. Gene ontology terms enriched for e-OPCs were cell cycle and development, for l-OPCs were extracellular matrix and cell adhesion, and for MOLs were myelination and cytoskeleton. The e-OPCs were mostly confined to the premyelinating fetal group, and the l-OPCs were most highly represented in the pediatric age group, corresponding to the peak age of myelination. Cells expressing a signature characteristic of l-OPCs were identified in the adult brain in situ using RNAScope. These findings highlight the transcriptomic variability in OL-lineage cells before, during, and after peak myelination and contribute to identifying novel pathways required to achieve remyelination.

2021-01-12 | GSE155488 | GEO

The oligodendrocyte "protrusiosome": Identification of compartmentalized enrichment of transcripts in newly-formed protrusions of oligodendrocyte precursor cells (OPC) by RNAseq

Project description:The oligodendrocyte "protrusiosome": Identification of compartmentalized enrichment of transcripts in newly-formed protrusions of oligodendrocyte precursor cells (OPC) by RNAseq

| PRJNA418248 | ENA

Identification of mRNAS enriched in endothelial cell protrusions

Project description:Deciphering the complex biology of cell migration is key to understand human-related disorders. During angiogenesis, endothelial cells engage in coordinated migration events to form new blood vessels from parental counterparts. However, while subcellular localisation of mRNAs and localised translation are fundamental steps between gene transcription and protein activity, whether local regulation of gene expression controls the complex morphogenetic process of angiogenesis has never been addressed. Here, we set out to investigate the cytoplasmic distribution of mRNAs in migratory endothelial cells. We isolated RNA from endothelial cell protrusions from their cell bodies and used RNA-sequencing to identify asymmetrically distributed transcripts. These studies identified a set of transcripts enriched in endothelial cell protrusions over cell bodies, which included classically protrusion-enriched mRNAs and other intriguing transcripts encoding proteins implicated in cell migration.

2020-09-07 | GSE133055 | GEO

Endothelin-1-Endothelin B complex contributes to oligodendrocyte differentiation and myelin deficits during preterm white matter injury

Project description:Preterm cerebral white matter injury (WMI), a major form of prenatal brain injury, may potentially be treated by oligodendrocyte (OL) precursor cell (OPC) transplantation. However, the defective differentiation of OPCs during WMI seriously hampers the clinical application of OPC transplantation. Thus, improving the ability of transplanted OPCs to differentiate is critical to OPC transplantation therapy for WMI. Here, we established a hypoxia-ischemia-induced preterm WMI model in mice and screened the molecules affected by WMI using single-cell RNA sequencing. We revealed that endothelin (ET)-1 and endothelin receptor B (ETB) were a pair of signaling molecules for the interaction between neurons and OPCs, and that preterm WMI led to an increase in the number of ETB-positive OPCs and premyelinating OLs. Furthermore, the maturation of OLs was reduced by knocking out ETB, but promoted by stimulating ET-1/ETB signaling. Our work reveals a new signaling module for neuron-OPC interaction and provides new insight for therapy targeting preterm WMI.

2023-03-04 | GSE225580 | GEO

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