GDE2-dependent activation of canonical Wnt signaling in neurons regulates oligodendrocyte maturation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA613136 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11341482_1.fastq.gz | Fastqsanger.gz | |||
| SRR11341482_2.fastq.gz | Fastqsanger.gz | |||
| SRR11341483_1.fastq.gz | Fastqsanger.gz | |||
| SRR11341483_2.fastq.gz | Fastqsanger.gz | |||
| SRR11341484_1.fastq.gz | Fastqsanger.gz |
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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.
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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 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.
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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) signaling underlies 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). Wild-type (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.
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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:Cellular maturation is an adaptive process essential for tissue formation and function, yet distinct from the initial steps of differentiation and cell fate specification. Understanding the regulation of cell maturation may inform underlying mechanisms of disease or new approaches to regenerative medicine. In the central nervous system, failed generation of mature oligodendrocytes contributes to numerous diseases including multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After differentiation, the transcription factor SOX6 redistributes from super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggesting that failed maturation contributes to disease pathology. Administration of a Sox6-targeting antisense oligonucleotide in postnatal mice drove precocious oligodendrocyte maturation. Our findings reveal that SOX6 governs oligodendrocyte maturation and that its targeting could inform therapeutic strategies for enhancing myelin regeneration in neurodevelopmental and neurodegenerative diseases.
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2023-09-01 | GSE182558 | GEO
Project description:Cellular maturation is an adaptive process essential for tissue formation and function, yet distinct from the initial steps of differentiation and cell fate specification. Understanding the regulation of cell maturation may inform underlying mechanisms of disease or new approaches to regenerative medicine. In the central nervous system, failed generation of mature oligodendrocytes contributes to numerous diseases including multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After differentiation, the transcription factor SOX6 redistributes from super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggesting that failed maturation contributes to disease pathology. Administration of a Sox6-targeting antisense oligonucleotide in postnatal mice drove precocious oligodendrocyte maturation. Our findings reveal that SOX6 governs oligodendrocyte maturation and that its targeting could inform therapeutic strategies for enhancing myelin regeneration in neurodevelopmental and neurodegenerative diseases.
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