Abstract W MP86: Microrna-146a Modulates Neurogenesis And Oligodendrogenesis After Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Xianshuang Liu ◽  
Chopp Michael ◽  
Xinli Wang ◽  
Li Zhang ◽  
Yisheng Cui ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Molecular Mechanisms ◽  
Neural Progenitor Cells ◽  
Target Genes ◽  
Artery Occlusion ◽  
Locked Nucleic Acid ◽  
Myelin Proteins ◽  
Oligodendrocyte Progenitor Cells ◽  
Marker Proteins

Background: Neurogenesis and oligodendrogenesis are associated with functional recovery after stroke. However, the molecules that regulate the generation of new neurons and oligodendrocytes have not been fully investigated. MicroRNAs (miRNAs) post-transcriptionally regulate gene expression. MiR-146a has been reported to regulate the immune response in cells, but the role of miR-146a in neural (NPCs) and oligodendrocyte progenitor cells (OPCs) remains unexplored. Methods and Results: Adult Wistar rats were subjected to right middle cerebral artery occlusion (MCAo). In situ hybridization using locked nucleic acid (LNA)probes against miR-146a showed that stroke considerably increased miR-146a density in the subventricular zone (SVZ, 19 ± 1 vs 6 ± 0.1 area/mm2 in non-MCAo group, p<0.05, n=4/group) and corpus callosum (24 ± 3 vs 8±1 area/mm2 in non-MCAo group) of the ischemic hemisphere. Quantitative RT-PCR also demonstrated a marked upregulation of miR-146a transcript in ischemic NPCs (8.5 fold), suggesting an important role in stroke-induced neurogenesis and oligodendrogenesis. To test its biological function, we over-expressed miR-146a in neural progenitor cells by transfection of miR-146a mimics using nucleofector and found that elevation of miR-146a significantly increased the percentage of Tuj1+ neuroblasts (5 ± 0.3 vs 1 ± 0.2%, p<0.05, n=6/group) and O4+ OPCs (10 ± 1 vs 4 ± 0.4%, p<0.05). Moreover, over-expression of miR-146a in primary cultured OPCs significantly increased several myelin proteins including MBP and PLP, and decreased levels of OPC marker proteins including PDGFRα and NG2, whereas attenuation of miR-146a by siRNA against miR-146a suppressed myelin proteins and augmented OPC marker proteins. Furthermore, miR-146a levels in the OPCs were inversely related to IRAK1 proteins, one of miR-146a target genes. Attenuation of IRAK1 in OPCs substantially increased myelin proteins, indicating that miR-146a mediates oligodendrocyte maturation via targeting IRAK1. Conclusion: Our data provide new insight into molecular mechanisms underlying stroke-induced neurogenesis and oligodendrogenesis by revealing a novel role of miR-146a in NPCs and OPCs, which has potential to be used as a new therapy for neurorecovery after stroke.

Abstract 141: The Microrna 17-92 Cluster in Neural Progenitor Cells is Required for Stroke-induced Neurogenesis and Gliogenesis

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Wanlong Pan ◽  
Xianshuang Liu ◽  
Xiaoming Zhang ◽  
Xinli Wang ◽  
Jiani Hu ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Molecular Mechanisms ◽  
Neural Progenitor Cells ◽  
Neural Progenitor ◽  
Artery Occlusion ◽  
Tamoxifen Treatment ◽  
Oligodendrocyte Progenitor Cells ◽  
Factor Inhibitor

Background: Molecular mechanisms underlying stroke-induced neurogenesis have not been fully investigated. The microRNA 17-92 cluster (miR17-92) regulates proliferation and differentiation of adult neural progenitor cells (NPCs). The present study investigated whether the miR17-92 cluster in NPCs is required for stroke-induced neurogenesis. Methods and Results: Mice with inducible and conditional knockdown of the miR17-92 cluster in nestin lineage NPCs (nestin-CreER T2 /miR17-92 -/- , 17-92-cKO, n=9) and wild-type litters (WT, n=9) were treated by tamoxifen. Administration of tamoxifen resulted in more than 60% reduction of individual members of the miR-17-92 cluster (miR-17: 1.0 vs 0.4; miR-19a: 1.0 vs 0.3; miR-19b: 1.0 vs 0.2; miR-20a: 1.0 vs 0.4; miR-92a: 1.0 vs 0.4 fold in WT, p<0.05) in NPCs localized to the subventricular zone (SVZ). Two days after termination of tamoxifen treatment, these mice were subjected to permanent right middle cerebral artery occlusion (MCAO) and sacrificed 28 days post-MCAo. Compared to WT mice, 17-92-cKO mice exhibited significant (p<0.05) reduction of proliferation of NPCs measured by the number of Ki67 + cells (226±43 vs 471±100 cells/mm 2 ) and the number of DCX + neuroblasts (11±2% vs 24±4% ) in the ischemic SVZ. Cultured NPCs harvested from ischemic cKO mice showed significant (p<0.05) reduction of BrdU + cells (37±2% vs 61±4% WT , n=3/group), Tuj1 + neuroblasts (5±0.2% vs 9±0.4% ), GFAP + cells (33±3% vs 53±2% ), and NG2 + oligodendrocyte progenitor cells (OPCs, 3±0.1% vs 5±0.5%). These in vivo and in vitro data indicate that reduction of the miR17-92 cluster suppresses stroke-induced neurogenesis and gliogenesis. Western blot analysis showed that miR17-92 cKO significantly (p<0.05) increased and reduced a cytoskeleton-associated protein, Enigma homolog1 (ENH1, 1.6 vs 1.0 fold), and its down-stream transcription factor, inhibitor of differentiation1 (ID1, 1.0 vs 0.6 fold), respectively. ENH1 is a putative target of the miR17-92 cluster. Conclusion: Our data indicate that the miR17-92 cluster in adult nestin lineage NPCs is required for stroke-induced neurongenesis and gliogenesis, and that the miR17-92 cluster possibly targets ENH1/ID1 signaling.

scholarly journals The role of m6A modification in the biological functions and diseases

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiulin Jiang ◽  
Baiyang Liu ◽  
Zhi Nie ◽  
Lincan Duan ◽  
Qiuxia Xiong ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Rna Modification ◽  
Biological Functions ◽  
Rna Methylation ◽  
Downstream Target ◽  
Different Types ◽  
M6a Rna Methylation

AbstractN6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

A Role of CPEB1 in the Modulation of Proliferation and Neuronal Maturation of Rat Primary Neural Progenitor Cells

2013 ◽  
Vol 38 (9) ◽  
pp. 1960-1972 ◽  
Author(s):  
Ki Chan Kim ◽  
Ji-Woon Kim ◽  
Chang Soon Choi ◽  
Sun Young Han ◽  
Jae Hoon Cheong ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Neural Progenitor Cells ◽  
Neural Progenitor ◽  
Neuronal Maturation

scholarly journals Discovery of MicroRNAs and Their Target Genes Related to Drought in Paulownia “Yuza 1” by High-Throughput Sequencing

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Minjie Deng ◽  
Yabing Cao ◽  
Zhenli Zhao ◽  
Lu Yang ◽  
Yanfang Zhang ◽  
...  
Keyword(s):  
Drought Stress ◽  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
Plant Hormone ◽  
Target Genes ◽  
Reference Data ◽  
Relevant Information ◽  
Putative Target

Understanding the role of miRNAs in regulating the molecular mechanisms responsive to drought stress was studied in Paulownia “yuza 1.” Two small RNA libraries and two degradome libraries were, respectively, constructed and sequenced in order to detect miRNAs and their target genes associated with drought stress. A total of 107 miRNAs and 42 putative target genes were identified in this study. Among them, 77 miRNAs were differentially expressed between drought-treated Paulownia “yuza 1” and the control (60 downregulated and 17 upregulated). The predicted target genes were annotated using the GO, KEGG, and Nr databases. According to the functional classification of the target genes, Paulownia “yuza 1” may respond to drought stress via plant hormone signal transduction, photosynthesis, and osmotic adjustment. Furthermore, the expression levels of seven miRNAs (ptf-miR157b, ptf-miR159b, ptf-miR398a, ptf-miR9726a, ptf-M2153, ptf-M2218, and ptf-M24a) and their corresponding target genes were validated by quantitative real-time PCR. The results provide relevant information for understanding the molecular mechanism of Paulownia resistance to drought and reference data for researching drought resistance of other trees.

scholarly journals NCAM regulates temporal specification of neural progenitor cells via profilin2 during corticogenesis

2019 ◽  
Vol 219 (1) ◽  
Author(s):  
Rui Huang ◽  
De-Juan Yuan ◽  
Shao Li ◽  
Xue-Song Liang ◽  
Yue Gao ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cortical Neurons ◽  
Actin Polymerization ◽  
Molecular Mechanisms ◽  
Neural Progenitor Cells ◽  
Cortical Development ◽  
Neural Progenitor ◽  
Neural Cell Adhesion ◽  
Fate Decision ◽  
Temporal Specification

The development of cerebral cortex requires spatially and temporally orchestrated proliferation, migration, and differentiation of neural progenitor cells (NPCs). The molecular mechanisms underlying cortical development are, however, not fully understood. The neural cell adhesion molecule (NCAM) has been suggested to play a role in corticogenesis. Here we show that NCAM is dynamically expressed in the developing cortex. NCAM expression in NPCs is highest in the neurogenic period and declines during the gliogenic period. In mice bearing an NPC-specific NCAM deletion, proliferation of NPCs is reduced, and production of cortical neurons is delayed, while formation of cortical glia is advanced. Mechanistically, NCAM enhances actin polymerization in NPCs by interacting with actin-associated protein profilin2. NCAM-dependent regulation of NPCs is blocked by mutations in the profilin2 binding site. Thus, NCAM plays an essential role in NPC proliferation and fate decision during cortical development by regulating profilin2-dependent actin polymerization.

scholarly journals STAT3 and STAT5 Activation in Solid Cancers

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1428 ◽  
Author(s):  
Sebastian Igelmann ◽  
Heidi Neubauer ◽  
Gerardo Ferbeyre
Keyword(s):  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Critical Role ◽  
Control Cell ◽  
Cytokine Signaling ◽  
Specific Gene ◽  
Mitochondrial Functions ◽  
Context Dependent

The Signal Transducer and Activator of Transcription (STAT)3 and 5 proteins are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context-dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association with survival in cancer patients. The molecular mechanisms that underpin the oncogenic activity of STAT3/5 signaling include the regulation of genes that control cell cycle and cell death. However, recent advances also highlight the critical role of STAT3/5 target genes mediating inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling, including tyrosine phosphatases, the sumo ligase Protein Inhibitor of Activated STAT3 (PIAS3), the E3 ubiquitin ligase TATA Element Modulatory Factor/Androgen Receptor-Coactivator of 160 kDa (TMF/ARA160), the miRNAs miR-124 and miR-1181, the Protein of alternative reading frame 19 (p19ARF)/p53 pathway and the Suppressor of Cytokine Signaling 1 and 3 (SOCS1/3) proteins. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated with STAT3/5 signaling, explaining their context-dependent association with tumor progression both in human cancers and animal models.

scholarly journals Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

2015 ◽  
Vol 112 (51) ◽  
pp. 15755-15760 ◽  
Author(s):  
Miyeon Choi ◽  
Seung Hoon Lee ◽  
Sung Eun Wang ◽  
Seung Yeon Ko ◽  
Mihee Song ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Nuclear Export ◽  
Hippocampal Neurons ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Calmodulin Kinase ◽  
Defective Mutant ◽  
Antidepressant Effects

Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II- and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamine-induced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine.

scholarly journals Ecology and molecular targets of hypermutation in the global microbiome

2020 ◽  
Author(s):  
Simon Roux ◽  
Blair G. Paul ◽  
Sarah C. Bagby ◽  
Michelle A. Allen ◽  
Graeme Attwood ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Distinct Type ◽  
Raw Material ◽  
Read Mapping ◽  
A Genome ◽  
And Function ◽  
Natural Communities ◽  
Cellular Genome

AbstractChanges in the sequence of an organism’s genome, i.e. mutations, are the raw material of evolution1. The frequency and location of mutations can be constrained by specific molecular mechanisms, such as Diversity-generating retroelements (DGRs)2–4. DGRs introduce mutations in specific target genes, and were characterized from several cultivated bacteria and bacteriophages2. Whilst a larger diversity of DGR loci has been identified in genomic data from environmental samples, i.e. metagenomes, the ecological role of these DGRs and their associated evolutionary drivers remain poorly understood5–7. Here we built and analyzed an extensive dataset of >30,000 metagenome-derived DGRs, and determine that DGRs have a single evolutionary origin and a universal bias towards adenine mutations. We further identified six major lineages of DGRs, each associated with a specific ecological niche defined as a genome type, i.e. whether the DGR is encoded on a viral or cellular genome, a limited set of taxa and environments, and a distinct type of target. Finally, we leverage read mapping and metagenomic time series to demonstrate that DGRs are consistently and broadly active, and responsible for >10% of all amino acid changes in some organisms at a conservative estimate. Overall, these results highlight the strong constraints under which DGRs diversify and expand, and elucidate several distinct roles these elements play in natural communities and in shaping microbial community structure and function in our environment.

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