The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration
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PROVIDER: PRJNA869830 | ENA |
REPOSITORIES: ENA
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Project description:The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration [RNA-seq]
| PRJNA869842 | ENA
Project description:The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration [ChIP-seq]
| PRJNA869843 | ENA
Project description:Axonal myelination is essential for neuronal function and health. In peripheral nerves, deficient myelination is responsible for the morbidity of various forms of inherited or acquired neuropathies, including Charcot-Marie-Tooth disease and diabetic neuropathy. Decades of research have uncovered a complex transcriptional and post-transcriptional program that co-ordinates the formation and maintenance of the myelin sheath. In contrast, much less is known about the functional role of post-translational modification (PTM) of proteins in this remarkable biogenic process. Neddylation, a PTM that involves the conjugation of the ubiquitin-like protein Nedd8 to protein targets, has recently emerged as a central and versatile regulator of many cellular processes, including gene transcription, metabolism, and cellular differentiation. In this study, we show that genetic and pharmacological inhibition of neddylation in vivo in developing Schwann cells lead to striking nerve defects that exhibit the classical hallmarks of a severe neuropathy, including gait abnormalities, muscle weakness, and hindlimb clasping, ultimately leading to early death. The mutant mice lack peripheral myelin and develop secondary axonal loss, and we demonstrate, at the mechanistic level, that neddylation regulates multiple critical myelination-related pathways. Together, our findings identify neddylation as a central regulatory hub of control of peripheral myelination and delineate the potential pathogenetic mechanisms in inherited human PNS disorders, characterized by mutations in genes related to the neddylation pathway.
2024-06-16 | PXD043917 | Pride
Project description:The myelin sheaths that surround the thick axons of the peripheral nervous system are produced by the highly specialized Schwann cells. Differentiation of Schwann cells and myelination occur in discrete steps. Each of these requires coordinated expression of specific proteins in a precise sequence, yet the regulatory mechanisms controlling protein expression during these events are incompletely understood. Here we report that Schwann cell-specific ablation of the enzyme Dicer1, which is required for the production of small non-coding regulatory microRNAs, fully arrests Schwann cell differentiation, resulting in early postnatal lethality. Dicer-/- Schwann cells had lost their ability to myelinate, yet were still capable of sorting axons. Both cell death and, paradoxically, proliferation of immature Schwann cells was vastly enhanced, suggesting that their terminal differentiation is triggered by growth-arresting regulatory microRNAs. Using microRNA microarrays, we identified 16 miRNAs that are upregulated upon myelination and whose expression is controlled by Dicer in Schwann cells. This set of microRNAs appears to drive Schwann cell differentiation and myelination of peripheral nerves, thereby fulfilling a crucial function for survival of the organism. Samples representing Schwann cell-specific ablation of the enzyme Dicer1 and wild type controls at developmental stages E17 and P4. Geometric mean-averaged data linked below as supplementary file.
2010-12-01 | E-GEOD-22023 | biostudies-arrayexpress
Project description:Here, we demonstrated that the signal transducer and activator of transcription 1 (Stat1) is essential for Schwann cell (SC) differentiation. To identify genes directly targeted by Stat1, we performed chromatin immunoprecipitation sequencing (ChIP-Seq) in differentiating rat SCs.
2023-09-11 | GSE211337 | GEO
Project description:To investigate the potential mechanisms of Stat1 regulation of Schwann cell (SC) differentiation, we performed a RNA sequencing (RNA-seq) of SCs grown under differentiation conditions treated with Stat1-siRNA or with non-targeting negative control siRNA (Scramble).
2023-09-11 | GSE211336 | GEO
Project description:The myelin sheaths that surround the thick axons of the peripheral nervous system are produced by the highly specialized Schwann cells. Differentiation of Schwann cells and myelination occur in discrete steps. Each of these requires coordinated expression of specific proteins in a precise sequence, yet the regulatory mechanisms controlling protein expression during these events are incompletely understood. Here we report that Schwann cell-specific ablation of the enzyme Dicer1, which is required for the production of small non-coding regulatory microRNAs, fully arrests Schwann cell differentiation, resulting in early postnatal lethality. Dicer-/- Schwann cells had lost their ability to myelinate, yet were still capable of sorting axons. Both cell death and, paradoxically, proliferation of immature Schwann cells was vastly enhanced, suggesting that their terminal differentiation is triggered by growth-arresting regulatory microRNAs. Using microRNA microarrays, we identified 16 miRNAs that are upregulated upon myelination and whose expression is controlled by Dicer in Schwann cells. This set of microRNAs appears to drive Schwann cell differentiation and myelination of peripheral nerves, thereby fulfilling a crucial function for survival of the organism.
2010-12-01 | GSE22023 | GEO
Project description:Myelination is essential for nervous system function. Schwann cells interact with neurons and with the basal lamina to sort and myelinate axons, using known receptors and signaling pathways. In contrast, the transcriptional control of axonal sorting and the role of mechano-transduction in myelination are largely unknown. Yap and Taz are effectors of the Hippo pathway that integrate chemical and mechanical signals in cells. Here, we describe a previously unknown role for the Hippo pathway in myelination. Using conditional mutagenesis in mice we show that Taz is required in Schwann cells for radial sorting and myelination. Yap is redundant with Taz as ablation of both Yap and Taz abolishes radial sorting. Yap/Taz regulate Schwann cell proliferation and transcription of basal lamina receptors, both necessary for proper radial sorting of axons, and subsequent myelination. These data link transcriptional effectors of the Hippo pathway and of mechanotransduction to myelin formation in Schwann cells.
2016-06-06 | GSE79115 | GEO
Project description:Myelin sheath formation in the peripheral nervous system is a complex event resulting from spatially and temporally regulated reciprocal interactions between the neuron and myelin-forming Schwann cells. Although many of the components of the sheath have been identified and well-characterized, our knowledge of the dynamic cellular and molecular processes and of the protein functional networks that participate in its formation is still weak. This paper describes a robust approach, combining transcriptomics, proteomics and immunocytochemistry analyses of myelinating dorsal root ganglion cultures derived from C57BL/6J mice, which can be exploited to identify protein networks, and their constituent modules, involved in peripheral nerve myelin formation. The approach allows distinguishing clear, reproducible and predictable differences between the structural properties of the cultures and their genome-wide and proteomic expression profiles at different stages of the myelination process. The expression profiles of selected neuronal and Schwann cell genes and proteins in the cultures reflect those observed in vivo, and the structural and ultrastructural properties and myelination schedule of the cultures closely resemble those observed in peripheral nerves in situ. The approach provides a unique and powerful tool to study comprehensive transcriptome and proteomic changes taking place simultaneously in Schwann cells and neurons during PNS myelination.
2015-08-16 | GSE60345 | GEO
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