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miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A

Microglia, the innate immune effector cells of the mammalian central nervous system (CNS), are involved in the development, homeostasis, and pathology of CNS. Microglia become activated in response to various insults and injuries and protect the CNS by phagocytosing the invading pathogens, dead neur...

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Autores principales: Gupta, Neelima, Jadhav, Shweta, Tan, Kai-Leng, Saw, Genevieve, Mallilankaraman, Karthik Babu, Dheen, S. Thameem
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253665/
https://www.ncbi.nlm.nih.gov/pubmed/32508597
http://dx.doi.org/10.3389/fncel.2020.00132
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author Gupta, Neelima
Jadhav, Shweta
Tan, Kai-Leng
Saw, Genevieve
Mallilankaraman, Karthik Babu
Dheen, S. Thameem
author_facet Gupta, Neelima
Jadhav, Shweta
Tan, Kai-Leng
Saw, Genevieve
Mallilankaraman, Karthik Babu
Dheen, S. Thameem
author_sort Gupta, Neelima
collection PubMed
description Microglia, the innate immune effector cells of the mammalian central nervous system (CNS), are involved in the development, homeostasis, and pathology of CNS. Microglia become activated in response to various insults and injuries and protect the CNS by phagocytosing the invading pathogens, dead neurons, and other cellular debris. Recent studies have demonstrated that the epigenetic mechanisms ensure the coordinated regulation of genes involved in microglial activation. In this study, we performed a microRNA (miRNA) microarray in activated primary microglia derived from rat pup’s brain and identified differentially expressed miRNAs targeting key genes involved in cell survival, apoptosis, and inflammatory responses. Interestingly, miR-142-3p, one of the highly up-regulated miRNAs in microglia upon lipopolysaccharide (LPS)-mediated activation, compared to untreated primary microglia cells was predicted to target Ca(2+)/calmodulin dependent kinase 2a (CAMK2A). Further, luciferase reporter assay confirmed that miR-142-3p targets the 3′UTR of Camk2a. CAMK2A has been implicated in regulating the expression of brain-derived neurotrophic factor (BDNF) and long-term potentiation (LTP), a cellular mechanism underlying memory and learning. Given this, this study further focused on understanding the miR-142-3p mediated regulation of the CAMK2A-BDNF pathway via Cyclic AMP-responsive element-binding protein (CREB) in activated microglia. The results revealed that CAMK2A was downregulated in activated microglia, suggesting an inverse relationship between miR-142-3p and Camk2a in activated microglia. Overexpression of miR-142-3p in microglia was found to decrease the expression of CAMK2A and subsequently BDNF through regulation of CREB phosphorylation. Functional analysis through shRNA-mediated stable knockdown of CAMK2A in microglia confirmed that the regulation of BDNF by miR-142-3p is via CAMK2A. Overall, this study provides a database of differentially expressed miRNAs in activated primary microglia and reveals that microglial miR-142-3p regulates the CAMK2A-CREB-BDNF pathway which is involved in synaptic plasticity.
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spelling pubmed-72536652020-06-05 miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A Gupta, Neelima Jadhav, Shweta Tan, Kai-Leng Saw, Genevieve Mallilankaraman, Karthik Babu Dheen, S. Thameem Front Cell Neurosci Cellular Neuroscience Microglia, the innate immune effector cells of the mammalian central nervous system (CNS), are involved in the development, homeostasis, and pathology of CNS. Microglia become activated in response to various insults and injuries and protect the CNS by phagocytosing the invading pathogens, dead neurons, and other cellular debris. Recent studies have demonstrated that the epigenetic mechanisms ensure the coordinated regulation of genes involved in microglial activation. In this study, we performed a microRNA (miRNA) microarray in activated primary microglia derived from rat pup’s brain and identified differentially expressed miRNAs targeting key genes involved in cell survival, apoptosis, and inflammatory responses. Interestingly, miR-142-3p, one of the highly up-regulated miRNAs in microglia upon lipopolysaccharide (LPS)-mediated activation, compared to untreated primary microglia cells was predicted to target Ca(2+)/calmodulin dependent kinase 2a (CAMK2A). Further, luciferase reporter assay confirmed that miR-142-3p targets the 3′UTR of Camk2a. CAMK2A has been implicated in regulating the expression of brain-derived neurotrophic factor (BDNF) and long-term potentiation (LTP), a cellular mechanism underlying memory and learning. Given this, this study further focused on understanding the miR-142-3p mediated regulation of the CAMK2A-BDNF pathway via Cyclic AMP-responsive element-binding protein (CREB) in activated microglia. The results revealed that CAMK2A was downregulated in activated microglia, suggesting an inverse relationship between miR-142-3p and Camk2a in activated microglia. Overexpression of miR-142-3p in microglia was found to decrease the expression of CAMK2A and subsequently BDNF through regulation of CREB phosphorylation. Functional analysis through shRNA-mediated stable knockdown of CAMK2A in microglia confirmed that the regulation of BDNF by miR-142-3p is via CAMK2A. Overall, this study provides a database of differentially expressed miRNAs in activated primary microglia and reveals that microglial miR-142-3p regulates the CAMK2A-CREB-BDNF pathway which is involved in synaptic plasticity. Frontiers Media S.A. 2020-05-21 /pmc/articles/PMC7253665/ /pubmed/32508597 http://dx.doi.org/10.3389/fncel.2020.00132 Text en Copyright © 2020 Gupta, Jadhav, Tan, Saw, Mallilankaraman and Dheen. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular Neuroscience
Gupta, Neelima
Jadhav, Shweta
Tan, Kai-Leng
Saw, Genevieve
Mallilankaraman, Karthik Babu
Dheen, S. Thameem
miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A
title miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A
title_full miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A
title_fullStr miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A
title_full_unstemmed miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A
title_short miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A
title_sort mir-142-3p regulates bdnf expression in activated rodent microglia through its target camk2a
topic Cellular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253665/
https://www.ncbi.nlm.nih.gov/pubmed/32508597
http://dx.doi.org/10.3389/fncel.2020.00132
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