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MiR-142-3p Regulates Cortical Oligodendrocyte Gene Co-expression Networks Associated with Tauopathy

ABSTRACT: 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 (WGCNA) 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE211162 | GEO | 2023/04/04

REPOSITORIES: GEO

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Project description:One way by which astrocytes modulate oligodendrocytes’ activity is by delivering neurotransmitters and leukemia inhibitory factor (Lif) in the medium that bind oligodendrocyte receptors. Most of these receptors are involved in intercellular Ca2+-signaling (ICS). However, not much is known about the interactions between myelination (MYE) and ICS genes and how astrocyte nearness modulates the oligodendrocyte genomic myelination fabric. We profiled the transcriptomes of immortalized oligodendrocyte precursor cells (Oli-neu) when cultured alone or co-cultured with cortical astrocytes. The astrocytes were plated in cell culture insert systems that did not allow formation of gap junction channels with oligodendrocytes but permitted exchange of soluble factors via the culture medium. Remarkably, astrocyte proximity induced a larger increase of the overall expression level and interlinkage of MYE genes than the differentiating 10d treatment with 1 mM dibutyryl cAMP that turns Oli-neu cells into myelin-associated glycoprotein-positive oligodendrocyte-like cells. Moreover, more MYE and ICS genes were turned on and fewer turned off by astrocyte proximity than by differentiating treatment. Lif receptor was up-regulated by astrocyte proximity but not by the differentiating treatment. We have identified the responsible transcriptomic networks by which the intercellular ICS gene web controls MYE gene web, with genes encoding the gap junction proteins (connexins, Cx) Cx29, Cx32 and Cx47 playing central roles. The novel Prominent Gene Analysis (that refines iteratively the functional webs to optimize the interconnectivity and expression stability of the associated genes) was used to select and rank the most relevant MYE and ICS genes and build the corresponding gene webs. Determine the modifications of the myelination transcriptome induced in Oli- neu control cells by differentiating treatment and proximity of cortical astrocytes. Four culture dishes of each of control, differentiated and in the astrocyte proximity Oli-neu cells were profiled using Duke mouse 30K and 36k oligonucleotide arrays in the "multiple yellow" hybrization design.

Project description:MicroRNAs (miRNAs, micro ribonucleic acids) are pivotal post-transcriptional regulators of gene expression. These endogenous small non-coding RNAs play significant roles in tumorigenesis and tumor progression. miR-142-3p expression is dysregulated in several breast cancer subtypes. We aimed at investigating the role of miR-142-3p in breast cancer cell invasiveness. Supported by transcriptomic Affymetrix array analysis and confirmatory investigations at the mRNA and protein level, we demonstrate that overexpression of miR-142-3p in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells leads to downregulation of WASL (Wiskott-Aldrichsyndrome-like, protein: N-WASP), Integrin-aV, RAC1, and CFL2, molecules implicated in cytoskeletal regulation and cell motility. ROCK2, IL6ST, KLF4, PGRMC2 and ADCY9 were identified as additional targets in a subset of cell lines. Decreased matrigel invasiveness was associated with the miR-142-3p-induced expression changes. Confocal immunofluorescence microscopy, nanoscale atomic force microscopy and digital holographic microscopy revealed a change in cell morphology as well as a reduced cell volume and size. A more cortical actin distribution and a loss of membrane protrusions were observed in cells overexpressing miR-142-3p. Luciferase activation assays confirmed direct miR-142-3p-dependent regulation of the 3'-untranslated region of ITGAV and WASL. siRNA-mediated depletion of ITGAV andWASL resulted in a significant reduction of cellular invasiveness, highlighting the contribution of these factors to the miRNA-dependent invasion phenotype. While knockdown of WASL significantly reduced the number of membrane protrusions compared to controls, knockdown of ITGAV resulted in a decreased cell volume, indicating differential contributions of these factors to the miR-142-3p-induced phenotype. Our data identify WASL, ITGAV and several additional cytoskeleton associated molecules as novel invasion-promoting targets of miR-142-3p in breast cancer.

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MiR-142-3p Regulates Cortical Oligodendrocyte Gene Co-expression Networks Associated with Tauopathy

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