miR-142-3p regulates cortical oligodendrocyte gene co-expression networks associated with tauopathy
| Autor: | Saverio Bellusci, Kenneth S. Kosik, Giovanni Coppola, Mohsen Ghanbari, Deborah Kim, Israel Hernandez, Kerstin Goth, Brent L. Fogel, Kathie J. Ngo, M. Arfan Ikram, Steven A. Kushner, Ci-Di Chen, Jason D Hinman, Riki Kawaguchi, Carmela R. Abraham |
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| Přispěvatelé: | Epidemiology, Radiology & Nuclear Medicine, Psychiatry |
| Rok vydání: | 2021 |
| Předmět: |
Central Nervous System
0301 basic medicine Population Gene regulatory network tau Proteins Biology Medical and Health Sciences Nerve Fibers Myelinated Cerebellar Cortex Mice 03 medical and health sciences 0302 clinical medicine SDG 3 - Good Health and Well-being microRNA Genetics medicine Animals Humans Gene Regulatory Networks RNA-Seq education Molecular Biology Genetics (clinical) Genetics & Heredity education.field_of_study Neurodegeneration General Medicine Biological Sciences medicine.disease Oligodendrocyte Disease Models Animal MicroRNAs Oligodendroglia 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation Tauopathies General Article Synaptic signaling Tauopathy Neuroscience 030217 neurology & neurosurgery Overlapping gene |
| Zdroj: | Hum Mol Genet Human molecular genetics, vol 30, iss 1 Human Molecular Genetics, 30(1), 103-118. Oxford University Press |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddaa252 |
| Popis: | Oligodendrocytes exist in a heterogenous state and are implicated in multiple neuropsychiatric diseases including dementia. Cortical oligodendrocytes are a glial population uniquely positioned to play a key role in neurodegeneration by synchronizing circuit connectivity but molecular pathways specific to this role are lacking. We utilized oligodendrocyte-specific translating ribosome affinity purification and RNA-seq (TRAP-seq) to transcriptionally profile adult mature oligodendrocytes from different regions of the central nervous system. Weighted gene co-expression network analysis reveals distinct region-specific gene networks. Two of these mature myelinating oligodendrocyte gene networks uniquely define cortical oligodendrocytes and differentially regulate cortical myelination (M8) and synaptic signaling (M4). These two cortical oligodendrocyte gene networks are enriched for genes associated with dementia including MAPT and include multiple gene targets of the regulatory microRNA, miR-142-3p. Using a combination of TRAP-qPCR, miR-142-3p overexpression in vitro, and miR-142-null mice, we show that miR-142-3p negatively regulates cortical myelination. In rTg4510 tau-overexpressing mice, cortical myelination is compromised, and tau-mediated neurodegeneration is associated with gene co-expression networks that recapitulate both the M8 and M4 cortical oligodendrocyte gene networks identified from normal cortex. We further demonstrate overlapping gene networks in mature oligodendrocytes present in normal cortex, rTg4510 and miR-142-null mice, and existing datasets from human tauopathies to provide evidence for a critical role of miR-142-3p-regulated cortical myelination and oligodendrocyte-mediated synaptic signaling in neurodegeneration. |
| Databáze: | OpenAIRE |
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