RNA-sequencing of Zdhhc5 knockout oligodendrocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE169247 | GEO | 2024/02/04
REPOSITORIES: GEO
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Project description:Myelin sheath is an important structure to maintain normal functions of the nerves in central nervous system. Protein palmitoylation has been established as a sorting determinant for the transport of myelin-forming proteins to the myelin membrane. However, its function in the regulation of oligodendrocyte development remains unknown. Here, we show that an Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases, DHHC5, is involved in the control of oligodendrocyte development. Loss of Zdhhc5 in oligodendrocytes inhibits myelination and remyelination by a reduction on total myelinating oligodendrocyte population. STAT3 is the primary substrate for DHHC5 palmitoylation in oligodendrocytes. Zdhhc5 ablation reduces STAT3 palmitoylation, and then suppresses STAT3 phosphorylation and activation. As a result of the decreased STAT3 transactivity, the transcription of the myelin-related and anti-apoptosis genes is therefore inhibited, leading to suppressed oligodendrocyte development and myelination. Our findings demonstrate the key role DHHC5 in the control of myelinogenesis.
2024-02-04 | GSE169248 | GEO
Project description:Two percent of all patients with X-linked intellectual disability (XLID) exhibit loss-of-function mutations in the palmitoylating enzyme, ZDHHC9. 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 oligodendrocytes, 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.
2023-08-21 | GSE236665 | GEO
Project description:Myelination by oligodendrocytes in the central nervous system (CNS) is essential for proper brain function, yet the molecular determinants that control this process remain poorly understood. The basic helix-loop-helix transcription factors Olig1 and Olig2 promote myelination, whereas bone morphogenetic protein (BMP) and Wnt/?-catenin signaling inhibit myelination. Here we show that these opposing regulators of myelination are functionally linked by the Olig1/2 common target Smad-interacting protein-1 (Sip1). We demonstrate that Sip1 is an essential modulator of CNS myelination. Sip1 represses differentiation inhibitory signals by antagonizing BMP receptor-activated Smad activity while activating crucial oligodendrocyte-promoting factors. Importantly, a key Sip1-activated target, Smad7, is required for oligodendrocyte differentiation and partially rescues differentiation defects caused by Sip1 loss. Smad7 promotes myelination by blocking the BMP- and ?-catenin-negative regulatory pathways. Thus, our findings reveal that Sip1-mediated antagonism of inhibitory signaling is critical for promoting CNS myelination and point to new mediators for myelin repair. ChIP-seq was performed to identify Olig2 direct target genes in oligodendrocytes during oligodendrocyte differentiation.
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Project description:The zinc finger protein ZFP24 is critical for CNS myelination. Nonetheless, the mechanism by which ZFP24 controls myelination is unknown. Here we use chromatin IP (ChIP) to map ZFP24 binding sites in oligodendrocyte progenitor cells (OPC) and differentiated oligodendrocytes (OLG). We find that ZFP24 directly binds the enhancer regions of genes important for oligodendrocyte differentiation and myelination and mediates their expression. We demonstrate that ZFP24 undergoes phosphorylation and dephosphorylation in oligodendrocyte lineage cells and that ZFP24 binding to DNA is controlled by its phosphorylated state such that only the non-phosphorylated form of the protein, predominantly found in mature oligodendrocytes, mediates expression of myelin protein genes. We have also identified key ZFP24 downstream target genes. Among these, we show that enforced expression of the crucial myelin transcription factor MYRF can rescue myelin proteins gene expression in ZFP24 -ablated cells. Our data also suggest that ZFP24 display overlapping genomic binding sites with the transcription factors MYRF, SOX10, and OLIG2 which are known to control terminal differentiation of oligodendrocytes. Though the human genome contains roughly 700 C2H2-containing zinc finger proteins, the DNA-binding sequences and the biological functions of the vast majority of them are unknown. Our findings provide a direct molecular mechanism by which dephosphorylation of ZFP24 mediates its binding to enhancer regions of genes important for oligodendrocyte differentiation and myelination, controls their expression, and as a result, regulates oligodendrocyte differentiation and CNS myelination.
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Project description:In the central nervous system, oligodendrocytes encase axons with myelin, a highly organized multilayered membrane structure. Myelin allows the rapid propagation of action potentials along the axons, while also supporting their mantainance metabolically. Fatty acids are basic building blocks for both glyco- and phospholipids, key constituents of cell membranes. Moreover, fatty acids can modify proteins via palmitoylation and activate transcriptional networks, e.g. through the PPARs transcription factors. Due to the high demand of membrane oligodendrocytes face to produce myelin, we hypothesized that they strongly rely upon fatty acid synthesis rather than mostly on their intake from the dietary pool. We tested this hypothesis by deleting the enzyme Fatty Acid Synthase specifically from neonatal oligodendrocyte progenitor cells, in vivo in C57Bl/6 olig2Cre FASN floxed mice. We addressed the consequences of this depletion on oligodendrocytes differentation and myelination potential in the central nervous system. In particular, we analyzed by RNA-seq how lack of FASN affected the transcriptome of optic nerves dissected from P14 mutant (olig2Cre FASN lox/lox) versus control (FASN lox/lox) mice.
2019-05-03 | GSE112725 | GEO
Project description:The transcriptional control of CNS myelin gene expression is poorly understood. Here we identify gene model 98, which we have named Myelin-gene Regulatory Factor (MRF), as a transcriptional regulator required for CNS myelination. Within the CNS, MRF is specifically expressed by postmitotic oligodendrocytes. MRF is a nuclear protein containing an evolutionarily conserved DNA binding domain homologous to a yeast transcription factor. Knockdown of MRF in oligodendrocytes by RNA interference prevents expression of most CNS myelin genes; conversely, overexpression of MRF within cultured oligodendrocyte progenitors or the chick spinal cord promotes expression of myelin genes. In mice lacking MRF within the oligodendrocyte lineage, pre-myelinating oligodendrocytes are generated but display severe deficits in myelin gene expression and fail to myelinate. These mice display severe neurological abnormalities, and die due to seizures during the third postnatal week. These findings establish MRF as a critical transcriptional regulator essential for oligodendrocyte maturation and CNS myelination. We used microarrays to compare cultured oligodendrocytes (differentiated in vitro for 4 days) from MRF conditional knockouts and control litteramates to look at the effects of MRF deficiency on myelin gene expression. Mouse OPCs grown in vitro in the presence of PDGF serve as a baseline for gene expression prior to differentiation.
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Project description:Understanding the regulation of oligodendrocyte development and myelination in the central nervous system (CNS) is essential, not only to facilitate myelin repair but also to define the role of oligodendrocytes in maintaining axonal integrity. In vitro studies have implicated astrocytes in influencing multiple aspects of oligodendrocytes and their precursors, however the in vivo role of astrocytes in myelination and myelin repair remain poorly defined. We show that astrocyte ablation during postnatal spinal cord development resulted in a concomitant delay in myelination, demonstrating a critical role for astrocytes in promoting developmental myelination. By contrast, in the adult CNS, localized ablation of astrocytes 2 days after a demyelinating insult resulted in increased numbers of oligodendrocytes and accelerated remyelination in both the spinal cord and the corpus callosum. Microarray analysis reveals astrocytic NF-kB signaling pathway as a major contributor to pathological events occurring after demyelination. We suggest that the localized functions of astrocytes are fundamentally different during developmental myelination and myelin repair. Astrocytes are critical for developmental myelination, however in a demyelinating environment they are detrimental to myelin repair.
2017-08-01 | GSE60276 | GEO
Project description:Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)—a transcription factor known to regulate expression of actin and actin regulators in other cell types—as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the fundamental role of SRF in oligodendrocyte lineage cells. Here we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in OPCs and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies a novel pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.
2024-02-23 | GSE241560 | GEO
Project description:Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)—a transcription factor known to regulate expression of actin and actin regulators in other cell types—as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the fundamental role of SRF in oligodendrocyte lineage cells. Here we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in OPCs and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies a novel pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.
2024-02-23 | GSE241559 | GEO
Project description:Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)—a transcription factor known to regulate expression of actin and actin regulators in other cell types—as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the fundamental role of SRF in oligodendrocyte lineage cells. Here we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in OPCs and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies a novel pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.
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