MicroRNAs Modulate Schwann Cell Response to Nerve Injury by Reinforcing Transcriptional Silencing of Dedifferentiation-Related Genes
Year: 2011
Type: article
Abstract: In the peripheral nervous system, Schwann cells (SCs) surrounding damaged axons undergo an injury response that is driven by an intricate transcriptional program and is critical for nerve regeneration. To examine whether these injury-induced changes in SCs are also regulated posttranscriptionally by miRNAs, we performed miRNA expression profiling of mouse sciatic nerve distal segment after crush injury. We also characterized the SC injury response in mice containing SCs with disrupted miRNA processing due to loss of Dicer. We identified 87 miRNAs that were expressed in mouse adult peripheral nerve, 48 of which were dynamically regulated after nerve injury. Most of these injury-regulated SC miRNAs were computationally predicted to inhibit drivers of SC dedifferentiation/proliferation and thereby re-enforce the transcriptional program driving SC remyelination. SCs deficient in miRNAs manifested a delay in the transition between the distinct differentiation states required to support peripheral nerve regeneration. Among the miRNAs expressed in adult mouse SCs, miR-34a and miR-140 were identified as functional regulators of SC dedifferentiation/proliferation and remyelination, respectively. We found that miR-34a interacted with positive regulators of dedifferentiation and proliferation such as Notch1 and Ccnd1 to control cell cycle dynamics in SCs. miR-140 targeted the transcription factor Egr2, a master regulator of myelination, and modulated myelination in DRG/SC cocultures. Together, these results demonstrate that SC miRNAs are important modulators of the SC regenerative response after nerve damage.
Source: Journal of Neuroscience
Institution: Washington University in St. Louis
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Funders: Institute of Clinical and Translational Sciences, Alvin J. Siteman Cancer Center, Hope Center for Neurological Disorders, National Institutes of Health, National Institute on Aging, National Cancer Institute, National Institute of Neurological Disorders and Stroke, U.S. National Library of Medicine, National Center for Research Resources
Awards: G1114310655, G12431752, G1820417268, G1861184163, G1925115500, G2025301497, Novel Bioinformatics Tools for Gene Regulatory Network Inference, G299873027, Regulating NAD Metabolism to Inhibit Axon Degeneration in Neurodegenerative Diseases, Regulation of Myelination by Egr2/Nab Protein Complexes, Washington University Center for Translational Neuroscience, Compromised LDH activity causes motor deficits and hastens ALS progression, Washington University Institute of Clinical and Translational Sciences (UL1), G8242737674, G8405709672, G9000007441, G9000063882, G9000282729, G9000319192, Compromised LDH activity causes motor deficits and hastens ALS progression, Cancer Center Support Grant, G953005567
OpenAlex ID: W2067432992