GDE2-dependent activation of canonical Wnt signaling in neurons regulates oligodendrocyte maturation
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ABSTRACT:
PROVIDER: PRJNA613136 | ENA |
REPOSITORIES: ENA
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Project description:Neurons and oligodendrocytes communicate to regulate oligodendrocyte development and ensure appropriate axonal myelination. Here, we show that Glycerophosphodiester phosphodiesterase 2 (GDE2) encodes a neuronal pathway that promotes oligodendrocyte maturation through the release of soluble neuronally-derived factors. Mice lacking global or neuronal GDE2 expression have reduced mature oligodendrocytes and myelin proteins but retain normal numbers of oligodendrocyte precursor cells (OPCs). WT OPCs cultured in conditioned medium (CM) from Gde2 null (Gde2KO) neurons exhibit delayed maturation, recapitulating in vivo phenotypes. Gde2KO neurons show robust reduction in canonical Wnt signaling and genetic activation of Wnt signaling in Gde2KO neurons rescues in vivo and in vitro oligodendrocyte maturation. Phosphacan, a known stimulant of oligodendrocyte maturation, is reduced in CM from Gde2KO neurons but is restored when Wnt signaling is activated. These studies identify GDE2 control of Wnt signaling as a neuronal pathway that signals to oligodendroglia to promote oligodendrocyte maturation.
2020-03-18 | GSE147144 | GEO
Project description:Neurons and oligodendrocytes communicate to regulate oligodendrocyte development and ensure appropriate axonal myelination. Here, we show that Glycerophosphodiester phosphodiesterase 2 (GDE2) encodes a neuronal pathway that promotes oligodendrocyte maturation through the release of soluble neuronally-derived factors. Mice lacking global or neuronal GDE2 expression have reduced mature oligodendrocytes and myelin proteins but retain normal numbers of oligodendrocyte precursor cells (OPCs). WT OPCs cultured in conditioned medium (CM) from Gde2 null (Gde2KO) neurons exhibit delayed maturation, recapitulating in vivo phenotypes. Gde2KO neurons show robust reduction in canonical Wnt signaling and genetic activation of Wnt signaling in Gde2KO neurons rescues in vivo and in vitro oligodendrocyte maturation. Phosphacan, a known stimulant of OL maturation, is reduced in CM from Gde2KOneurons but is restored when Wnt signaling is activated. These studies identify GDE2 control of Wnt signaling as a neuronal pathway that signals to oligodendroglia to promote oligodendrocyte maturation.
2021-09-09 | PXD018080 | Pride
Project description: Not available
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Project description:Mammalian cells respond to insufficient oxygen through transcriptional regulators called hypoxia-inducible factors (HIFs). Although transiently protective, prolonged HIF activity drives distinct pathological responses in different tissues. Using a model of chronic HIF1a accumulation in pluripotent-stem-cell-derived oligodendrocyte progenitors (OPCs), we demonstrate that HIF1a activates non-canonical targets to impair generation of oligodendrocytes from OPCs. HIF1a activated a unique set of genes in OPCs through interaction with the OPC-specific transcription factor OLIG2. Non-canonical targets, including Ascl2 and Dlx3, were sufficient to block differentiation through suppression of the oligodendrocyte regulator Sox10. Chemical screening revealed that inhibition of MEK/ERK signaling overcame the HIF1a-mediated block in oligodendrocyte generation by restoring Sox10 expression without affecting canonical HIF1a activity. MEK/ERK inhibition also drove oligodendrocyte formation in hypoxic regions of human oligocortical spheroids. This work defines mechanisms by which HIF1a impairs oligodendrocyte formation and establishes that cell-type-specific HIF1a targets perturb cell function in response to low oxygen.
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Project description:Mammalian cells respond to insufficient oxygen through transcriptional regulators called hypoxia-inducible factors (HIFs). Although transiently protective, prolonged HIF activity drives distinct pathological responses in different tissues. Using a model of chronic HIF1a accumulation in pluripotent-stem-cell-derived oligodendrocyte progenitors (OPCs), we demonstrate that HIF1a activates non-canonical targets to impair generation of oligodendrocytes from OPCs. HIF1a activated a unique set of genes in OPCs through interaction with the OPC-specific transcription factor OLIG2. Non-canonical targets, including Ascl2 and Dlx3, were sufficient to block differentiation through suppression of the oligodendrocyte regulator Sox10. Chemical screening revealed that inhibition of MEK/ERK signaling overcame the HIF1a-mediated block in oligodendrocyte generation by restoring Sox10 expression without affecting canonical HIF1a activity. MEK/ERK inhibition also drove oligodendrocyte formation in hypoxic regions of human oligocortical spheroids. This work defines mechanisms by which HIF1a impairs oligodendrocyte formation and establishes that cell-type-specific HIF1a targets perturb cell function in response to low oxygen.
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Project description:Mammalian cells respond to insufficient oxygen through transcriptional regulators called hypoxia-inducible factors (HIFs). Although transiently protective, prolonged HIF activity drives distinct pathological responses in different tissues. Using a model of chronic HIF1a accumulation in pluripotent-stem-cell-derived oligodendrocyte progenitors (OPCs), we demonstrate that HIF1a activates non-canonical targets to impair generation of oligodendrocytes from OPCs. HIF1a activated a unique set of genes in OPCs through interaction with the OPC-specific transcription factor OLIG2. Non-canonical targets, including Ascl2 and Dlx3, were sufficient to block differentiation through suppression of the oligodendrocyte regulator Sox10. Chemical screening revealed that inhibition of MEK/ERK signaling overcame the HIF1a-mediated block in oligodendrocyte generation by restoring Sox10 expression without affecting canonical HIF1a activity. MEK/ERK inhibition also drove oligodendrocyte formation in hypoxic regions of human oligocortical spheroids. This work defines mechanisms by which HIF1a impairs oligodendrocyte formation and establishes that cell-type-specific HIF1a targets perturb cell function in response to low oxygen.
2020-10-20 | GSE143472 | GEO
Project description:Up-regulation of canonical Wnt signaling has been implicated in liver fibrosis and cancer. To determine canonical Wnt target genes potentially implicated in these diseases, we performed microarray analysis of culture-activated rat hepatic stellate cells (HSCs) treated with canonical Wnt inhibitors, DKK-1, ICG-001, or FJ9.
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Project description:The high-mobility-group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. Here we deciphered the role of the high mobility group AT-hook protein 2 (HMGA2) during lung development by analyzing the lung of Hmga2 deficient mice (Hmga2-/-).We found that Hmga2 is expressed in the mouse embryonic lung at the distal airways. Analysis of Hmga2-/- mice showed that Hmga2 is required for proper cell proliferation and distal epithelium differentiation during embryonic lung development. Hmga2 knockout (KO) led to enhanced canonical WNT signaling due to an increased expression of secreted WNT glycoproteins Wnt2b, Wnt7b and Wnt11 as well as a reduction of the WNT signaling antagonizing proteins GATA6 (GATA binding protein 6) and FZD2 (frizzled homolog 2). Comparison of Hmga2-/- with Hmga2+/+ mice by Affymetrix microarray-based expression analysis of embryonic lung revealed an increased expression of genes whose products participate in cell cycle and canonical Wnt signaling. Affymetrix microarray transcriptome analysis of Hmga2-/- and Hmga2+/+ embryonic lung (E18.5) was performed and analyzed
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Project description:Oligodendrocytes are responsible for myelin formation and axonal trophic support in the vertebrate CNS. While a number of factors have been discovered that regulate oligodendrocyte lineage progression, the exact molecular mechanisms involved in this process remain unclear. Emerging studies have shown that N6-methyladenosine (m6A), the most common internal RNA modification of mammalian mRNA, plays a critical role in various developmental processes. In this study, we demonstrate that oligodendrocyte lineage progression is accompanied by changes in m6A modification on numerous transcripts. In vivo conditional inactivation in oligodendrocyte lineage cells of an essential m6A writer component, METTL14, results in decreased oligodendrocyte numbers and CNS hypomyelination, although oligodendrocyte precursor cell (OPC) numbers are normal. In vitro Mettl14 ablation disrupts post-mitotic oligodendrocyte maturation. In addition, Mettl14 ablation has distinct effects on OPC and oligodendrocyte transcriptomes. Together, our findings indicate that dynamic RNA methylation plays a critical regulatory role in oligodendrocyte development and CNS myelination.
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Project description:This experiment compared the expression of mRNAs and noncoding RNAs during neuronal-glial fate specification and oligodendrocyte lineage maturation. The primary aim of the experiment was to identify ncRNAs that were differentially expressed during this process.
2010-01-07 | E-TABM-874 | biostudies-arrayexpress