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Soluble Neuregulin1 is a negative regulator of myelination

ABSTRACT: Peripheral nerves are characterized by the ability to regenerate after injury. The activity of Schwann cells is fundamental for all steps of peripheral nerve regeneration: immediately after injury they de-differentiate, remove myelin debris, proliferate and repopulate the injured nerve. Neuregulin1 (NRG1) is a factor strongly up-regulated and released by Schwann cells immediately after nerve injury, known to play an important role for their de-differentiation, proliferation and survival. Nevertheless, up to now, the global analysis of the genes regulated by NRG1 was not performed. For this reason, we planned a deep RNA sequencing to generate a transcriptome database and identify all the genes regulated following stimulation of primary adult rat Schwann cells with soluble recombinant NRG1. Interestingly, the gene ontology analysis of the transcriptome shows that NRG1 regulates genes belonging to categories strongly regulated in the peripheral nerve immediately following injury. In particular, NRG1 strongly inhibits the expression of genes involved in myelination and in glial cell differentiation, suggesting that NRG1 plays a fundamental role in the de-differentiation (or “trans-differentiation”) process of Schwann cells from a myelinating to a repair phenotype. Moreover, NRG1 inhibits genes involved in the apoptotic process, therefore promoting cell survival, and up-regulates genes positively regulating the ribosomal RNA processing, thus suggesting that NRG1 actively stimulates new protein expression. This transcriptome analysis demonstrates that NRG1, which is strongly up-regulated immediately after injury, drives the expression of many important genes, thus playing a major role in the regeneration process.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE104324 | GEO | 2018/05/22

REPOSITORIES: GEO

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Project description:To shed light on the early processes of immune response to peripheral nerve injury, we first used genome-wide transcriptional profiling and bioinformatics (Ingenuity, NextBio) pathway analyses of the proximal (P; regenerating) and distal (D; degenerating) nerve stumps at day 1 in the sciatic nerve axotomy model in rats. We identified a number of specific immunomodulatory genes and pathways that were regulated shortly post-injury in both the P and D segments, including all members of the interleukin (IL), chemokine, tumor necrosis factor (TNF), matrix metalloproteinase (MMP), toll-like receptor (TLR), tissue inhibitor of metalloproteinase (TIMP), ion channel and myosin families. Immunomodulatory calcium-binding S100A8 and S100A9 were the top up-regulated genes in both the D and P segments. In cultured Schwann cells stimulated with the purified S100A8/A9 heterodimer we recorded a high level of similarity of the activated genes and pathways with that of the injured nerve, especially in the activation of the chemokine and cytokine gene networks that support agranulocyte and granulocyte chemotaxis, adhesion, transmigration and rolling signaling pathways. We also confirmed activation of multiple cell death related gene networks supporting TNFR1, natural killer cell receptor and death receptor apoptosis signaling in the D stump, and the gluconeogenesis/glycolysis and cytoskeletal motility signaling in the P stump, corroborated by activation of ERK, PI3K and JNK kinase pathways. As compared to the D segment, multiple additional pathways were more efficiently upregulated in the P stump, including the IL-6 and -17, MMP-9, calcium, activated agranulocyte, leukocyte rolling and glutathione-mediated detoxification signaling pathways. These data suggest that shortly after nerve injury, upregulation of S100A8/A9 is responsible for the expression and release of chemokines and cytokines by Schwann cells, necessary to generate the initial chemotactic gradient and guide the hematogenous immune cells into the injury site. Gene expression profiling of total RNAs extracted from injured and non-injured rat sciatic nerves, and primary rat Schwann cells stimulated with S100A8/A9 proteins

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Soluble Neuregulin1 is a negative regulator of myelination

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