Mitf is a Schwann Cell Sensor of Axonal Integrity that Drives Nerve Repair
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA905054 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22404100_1.fastq.gz | Fastqsanger.gz | |||
| SRR22404100_2.fastq.gz | Fastqsanger.gz | |||
| SRR22404101_1.fastq.gz | Fastqsanger.gz | |||
| SRR22404101_2.fastq.gz | Fastqsanger.gz | |||
| SRR22404102_1.fastq.gz | Fastqsanger.gz |
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Project description:Here we identify Mitf as a transcriptional sensor of axon damage under the control of Nrg-ErbB-PI3K-PI5K-mTorc2 signaling. Mitf regulates a core transcriptional program for generating functional repair Schwann cells following injury and during peripheral neuropathies caused by CMT4J and CMT4D. In the absence of Mitf, core genes for epithelial-to-mesenchymal transition, metabolism and dedifferentiation are misexpressed and nerve repair is disrupted. Taken together, our findings demonstrate that Schwann cells monitor axonal health using a phosphoinositide signaling system that controls Mitf, which is critical for activating cellular plasticity and counteracting neural disease. We performed gene expression profiling analysis using data obtained from RNA-seq of sciatic nerves from Mitf mutant mice in both control and injury experiments as well as in Ndrg1 and Egr2Cre models mutants.
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Project description:The peripheral nervous system (PNS) regenerates after injury. However regeneration is often compromised in case of large lesions, the speed of axon reconnection to their target being critical for successful functional recovery. After injury, mature Schwann cells (SCs) convert into repair cells that foster axonal regrowth, and redifferentiate to rebuild myelin. These processes require the regulation of several transcription factors, but the driving mechanisms remain partially understood. Here, we identify an early response to injury controlled by histone deacetylase (HDAC)2, which coordinates the action of other chromatin-remodeling enzymes to induce the upregulation of Oct6, a key transcription factor for Schwann cell development. Inactivating this mechanism using mouse genetics allows earlier conversion into repair cells and leads to faster axonal regrowth, but impairs remyelination. Consistently, short-term HDAC1/2 inhibitor treatment early after lesion accelerates functional recovery and enhances regeneration, thereby identifying a new therapeutic strategy to improve PNS regeneration after lesion.
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Project description:After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during the chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes a significant clinical problem. We find that aging and chronically denervated repair cells express reduced c-Jun protein and the regenerative support provided by these cells is also reduced. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to that in controls. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. These experiments reveal that a common mechanism, reduced c-Jun in repair cells, underlies two major reasons for regeneration failure in the PNS. They underscore the central importance of Schwann cell c-Jun as a regulator of nerve repair, and point to molecular pathways that can be manipulated for improving the clinical outcome of nerve injuries.
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Project description:Elucidating the genes regulated during cell-cell communication remains fascinating considering the importance of cell recognition and downstream signaling through development and in many diseases. In the peripheral nervous system, the interaction between Schwann cells (SCs) and axons is crucial as it allows their survival and induces SCs to differentiate and engage a process of myelination. To get further insight the molecular mechanisms resulting from this cell interaction, comparative gene analysis between SCs and SCs co-cultured with DRG neurons were performed and led us to identify a set of 32 genes regulated in SCs in the early stage of neuron-SC contact. Expression of several candidates were analyzed by QPCR during development and we demonstrate using a blocking antibody approach in an in vitro myelination assay that one candidate was not only upregulated in response to axonal contact but also controls peripheral myelination. Three biological replicates each in dye swap for 22k slides and two biological replicates each in dye swap for NeuroDev2
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Project description:Elucidating the genes regulated during cell-cell communication remains fascinating considering the importance of cell recognition and downstream signaling through development and in many diseases. In the peripheral nervous system, the interaction between Schwann cells (SCs) and axons is crucial as it allows their survival and induces SCs to differentiate and engage a process of myelination. To get further insight the molecular mechanisms resulting from this cell interaction, comparative gene analysis between SCs and SCs co-cultured with DRG neurons were performed and led us to identify a set of 32 genes regulated in SCs in the early stage of neuron-SC contact. Expression of several candidates were analyzed by QPCR during development and we demonstrate using a blocking antibody approach in an in vitro myelination assay that one candidate was not only upregulated in response to axonal contact but also controls peripheral myelination.
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Project description:The purpose of the present study is to influence of CA coating on immortalized Schwann cells in vitro in comparison to standard culture conditions as well as to laminin as a positive standard. CA is a homopolymer of polysialic acid (PSA), which has â attached to the neuronal cell adhesion molecule (NCAM) â emerged as particulate attractive candidate for promoting morphological plasticity of axonal processes during axonal path finding and activity-dependent remodelling. For this purpose self-spotted microarrays with 352 neurospecific genes were hybridized with mRNA from immortalized Schwann cells cultivated on different coating conditions: In order to enable a comprehensive comparison to the established coating material laminin as well as to standard coating conditions (cultivation on the cell culture surface) a loop-design has been chosen, which is based on the dye-swap design and facilitates a direct comparison of the different states. Results from 3 microarrays are summarized in this study. The samples originate from different coatings. Microarrays were hybridized in a loop design with one common reference using a dye swap approach.
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Project description:The purpose of the present study is to influence of CA coating on immortalized Schwann cells in vitro in comparison to standard culture conditions as well as to laminin as a positive standard. CA is a homopolymer of polysialic acid (PSA), which has – attached to the neuronal cell adhesion molecule (NCAM) – emerged as particulate attractive candidate for promoting morphological plasticity of axonal processes during axonal path finding and activity-dependent remodelling. For this purpose self-spotted microarrays with 352 neurospecific genes were hybridized with mRNA from immortalized Schwann cells cultivated on different coating conditions: In order to enable a comprehensive comparison to the established coating material laminin as well as to standard coating conditions (cultivation on the cell culture surface) a loop-design has been chosen, which is based on the dye-swap design and facilitates a direct comparison of the different states.
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