Functionally distinct subgroups of Oligodendrocyte precursor cells integrate neural activity and execute myelin formation
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ABSTRACT:
PROVIDER: PRJNA546235 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9198640.fastq.gz | Fastqsanger.gz | |||
| SRR9198650.fastq.gz | Fastqsanger.gz | |||
| SRR9198660.fastq.gz | Fastqsanger.gz | |||
| SRR9198670.fastq.gz | Fastqsanger.gz | |||
| SRR9198680.fastq.gz | Fastqsanger.gz |
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Project description:Neuronal activity can regulate the formation of new myelin by controlling division and differentiation of oligodendrocyte precursor cells (OPCs). If activity directly instructs OPCs to differentiate or whether this process underlies a more complex regulation in unclear, because it is not known if OPCs with different functions exist. By following lineage formation of individual OPC clones, single cell RNA sequencing, in vivo calcium imaging and manipulation of neural activity, we show that OPCs in the zebrafish spinal cord can be divided into two functional entities. One subgroup forms elaborate process networks and exhibits a high degree of calcium signalling activity, but infrequently differentiates, despite contact with permissive axons. Instead, these OPCs can divide in an activity and calcium dependent manner to produce another subgroup of OPCs, which readily differentiates and which shows less elaborate, more dynamic processes, and less calcium signaling activity. Our data reveal functional diversity within the OPC population in responding to neural activity and show that activity regulates proliferation of a subset of OPCs that is distinct from the cells that will differentiate, with implications for myelin development, plasticity, and repair.
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Project description:Recent reports have revealed that oligodendrocyte precursor cells (OPCs) are heterogeneous. It remains unclear whether such heterogeneity reflects different subtypes of cells with distinct functions or instead reflects transiently acquired states of cells with the same function. By integrating lineage formation of individual OPC clones, single-cell transcriptomics, calcium imaging and neural activity manipulation, we show that OPCs in the zebrafish spinal cord can be divided into two functionally distinct groups. One subgroup forms elaborate networks of processes and exhibits a high degree of calcium signaling, but infrequently differentiates despite contact with permissive axons. Instead, these OPCs divide in an activity- and calcium-dependent manner to produce another subgroup, with higher process motility and less calcium signaling and that readily differentiates. Our data show that OPC subgroups are functionally diverse in their response to neurons and that activity regulates the proliferation of a subset of OPCs that is distinct from the cells that generate differentiated oligodendrocytes.
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Project description:The notion that myelin remains static during adulthood has been challenged in recent years, and it is increasingly recognized that myelin may be altered by physiological events occurring outside of the central nervous system resulting in changes to cognition and behavior. The consequences of influenza A virus infection on oligodendrocytes in the adult mouse were investigated. Transcriptomic analysis revealed global downregulation and subsequent recovery of oligodendrocyte-specific transcripts in response to peripheral viral infection. Infection neither affected myelin thickness nor oligodendrocyte survival in the mPFC but altered the oligodendrocyte proteome and increased a disease-specific marker associated with oligodendrocyte stress. Furthermore, shot-gun lipidomic analysis revealed that infection altered the lipid profile in the prefrontal cortex as well as in purified brain myelin. Finally, treatment with the CSF1R antagonist GW2580 suppressed glial activation and partially restored oligodendrocyte-specific transcripts to baseline levels during infection. Together, these findings show that peripheral immunological challenge altered oligodendrocyte physiology.
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Project description:One way by which astrocytes modulate oligodendrocytes’ activity is by delivering neurotransmitters and leukemia inhibitory factor (Lif) in the medium that bind oligodendrocyte receptors. Most of these receptors are involved in intercellular Ca2+-signaling (ICS). However, not much is known about the interactions between myelination (MYE) and ICS genes and how astrocyte nearness modulates the oligodendrocyte genomic myelination fabric. We profiled the transcriptomes of immortalized oligodendrocyte precursor cells (Oli-neu) when cultured alone or co-cultured with cortical astrocytes. The astrocytes were plated in cell culture insert systems that did not allow formation of gap junction channels with oligodendrocytes but permitted exchange of soluble factors via the culture medium. Remarkably, astrocyte proximity induced a larger increase of the overall expression level and interlinkage of MYE genes than the differentiating 10d treatment with 1 mM dibutyryl cAMP that turns Oli-neu cells into myelin-associated glycoprotein-positive oligodendrocyte-like cells. Moreover, more MYE and ICS genes were turned on and fewer turned off by astrocyte proximity than by differentiating treatment. Lif receptor was up-regulated by astrocyte proximity but not by the differentiating treatment. We have identified the responsible transcriptomic networks by which the intercellular ICS gene web controls MYE gene web, with genes encoding the gap junction proteins (connexins, Cx) Cx29, Cx32 and Cx47 playing central roles. The novel Prominent Gene Analysis (that refines iteratively the functional webs to optimize the interconnectivity and expression stability of the associated genes) was used to select and rank the most relevant MYE and ICS genes and build the corresponding gene webs. Determine the modifications of the myelination transcriptome induced in Oli- neu control cells by differentiating treatment and proximity of cortical astrocytes. Four culture dishes of each of control, differentiated and in the astrocyte proximity Oli-neu cells were profiled using Duke mouse 30K and 36k oligonucleotide arrays in the "multiple yellow" hybrization design.
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Project description:Experimental autoimmune encephalomyelitis (EAE)-susceptible DA and EAE-resistant congenic R23 rats were immunized with myelin oligodendrocyte glycoprotein (MOG) to induce an autoimmune response.<br><br>Seven days later draining inguinal lymph nodes were removed. 2 conditions were examined: 'ex vivo' and 'MOG restimulated', which involved 24hrs of incubation with an encephalogenic MOG 91-108 peptide.<br><br>
2010-12-31 | E-MEXP-2703 | biostudies-arrayexpress
Project description:Experimental autoimmune encephalomyelitis (EAE)-susceptible DA and EAE-resistant PVG rats were immunized with myelin oligodendrocyte glycoprotein (MOG) to induce an autoimmune response.<br>Seven days later draining inguinal lymph nodes were removed. 2 conditions were examined: 'ex vivo' and 'MOG restimulated', which involved 24hrs of incubation with an encephalogenic MOG 91-108 peptide.
2009-11-01 | E-MEXP-2237 | biostudies-arrayexpress
Project description:Two percent of all patients with X-linked intellectual disability (XLID) exhibit loss-of-function mutations in the palmitoylating enzyme, ZDHHC91,2. One of the main anatomical deficits observed in these patients is a decrease in corpus callosum volume and a disruption of white matter integrity. We demonstrated that ablation of Zdhhc9 in mice substantially impairs the maturation of ligodendrocytes, resulting in fewer mature, myelinating oligodendrocytes, higher numbers of oligodendrocyte progenitor cells and a decrease in the density of myelinated axons. Ultrastructural analysis of the remaining myelinated axons in the corpus callosum revealed further disruptions in myelin integrity. RNA sequencing and proteomic analyses revealed a concomitant decrease in the expression of genes and proteins involved in lipid metabolism, cholesterol synthesis and myelin compaction. These results reveal a previously underappreciated and fundamental role for ZDHHC9 and protein palmitoylation in regulating oligodendrocyte differentiation and myelinogenesis and provide mechanistic insights into the deficits observed in white matter volume in patients with mutations in ZDHHC9.
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Project description:Inadequate remyelination of brain white matter lesions has been associated with a failure of oligodendrocyte precursors to differentiate into mature, myelin-producing cells. In order to better understand which genes play a specific role in oligodendrocyte differentiation we performed time dependent, genome-wide gene expression studies of mouse Oli-neu cells as they differentiate into myelin basic protein-producing cells, following treatment with three different agents. Our data indicate that different inducers activate distinct pathways that ultimately converge into the differentiated state where regulated gene sets overlap maximally. In order to also gain insight into the functional role of genes that are regulated in this process, we silenced 88 of these genes using siRNA, and identified multiple repressors of spontaneous differentiation of Oli-neu, most of which were confirmed in rat primary oligodendrocyte precursors cells. Among these repressors were CNPase, a well-known myelin constituent, and three phosphatases, each known to negatively control MAP kinase cascades. We show that a novel inhibitor for one of the identified genes, dual-specificity phosphatase DUSP10/MKP5, was also capable of inducing oligodendrocyte differentiation in primary oligodendrocyte precursors. Oligodendrocytic differentiation feedback loops may therefore yield pharmacological targets to treat disease related to dysfunctional myelin deposition Experiment Overall Design: triplicates for 3 times points 10h, 24h, 72h in 6 conditions, Forskolin, Insulin, Dexamethasone, Retinoic Acid, PD174265, Untreated. Arrays were done in two distinct experiments 1 and 2. Some replicates are missing because of lab operating issues
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