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Nerve Growth Factor Neutralization Promotes Oligodendrogenesis by Increasing miR-219a-5p Levels

In the brain, the neurotrophin Nerve growth factor (NGF) regulates not only neuronal survival and differentiation, but also glial and microglial functions and neuroinflammation. NGF is known to regulate oligodendrogenesis, reducing myelination in the central nervous system (CNS). In this study, we f...

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Autores principales: Brandi, Rossella, Fabiano, Marietta, Giorgi, Corinna, Arisi, Ivan, La Regina, Federico, Malerba, Francesca, Turturro, Sabrina, Storti, Andrea Ennio, Ricevuti, Flavia, Amadio, Susanna, Volontè, Cinzia, Capsoni, Simona, Scardigli, Raffaella, D’Onofrio, Mara, Cattaneo, Antonino
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920049/
https://www.ncbi.nlm.nih.gov/pubmed/33669304
http://dx.doi.org/10.3390/cells10020405
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author Brandi, Rossella
Fabiano, Marietta
Giorgi, Corinna
Arisi, Ivan
La Regina, Federico
Malerba, Francesca
Turturro, Sabrina
Storti, Andrea Ennio
Ricevuti, Flavia
Amadio, Susanna
Volontè, Cinzia
Capsoni, Simona
Scardigli, Raffaella
D’Onofrio, Mara
Cattaneo, Antonino
author_facet Brandi, Rossella
Fabiano, Marietta
Giorgi, Corinna
Arisi, Ivan
La Regina, Federico
Malerba, Francesca
Turturro, Sabrina
Storti, Andrea Ennio
Ricevuti, Flavia
Amadio, Susanna
Volontè, Cinzia
Capsoni, Simona
Scardigli, Raffaella
D’Onofrio, Mara
Cattaneo, Antonino
author_sort Brandi, Rossella
collection PubMed
description In the brain, the neurotrophin Nerve growth factor (NGF) regulates not only neuronal survival and differentiation, but also glial and microglial functions and neuroinflammation. NGF is known to regulate oligodendrogenesis, reducing myelination in the central nervous system (CNS). In this study, we found that NGF controls oligodendrogenesis by modulating the levels of miR-219a-5p, a well-known positive regulator of oligodendrocyte differentiation. We exploited an NGF-deprivation mouse model, the AD11 mice, in which the postnatal expression of an anti-NGF antibody leads to NGF neutralization and progressive neurodegeneration. Notably, we found that these mice also display increased myelination. A microRNA profiling of AD11 brain samples and qRT-PCR analyses revealed that NGF deprivation leads to an increase of miR-219a-5p levels in hippocampus and cortex and a corresponding down-regulation of its predicted targets. Neurospheres isolated from the hippocampus of AD11 mice give rise to more oligodendrocytes and this process is dependent on miR-219a-5p, as shown by decoy-mediated inhibition of this microRNA. Moreover, treatment of AD11 neurospheres with NGF inhibits miR-219a-5p up-regulation and, consequently, oligodendrocyte differentiation, while anti-NGF treatment of wild type (WT) oligodendrocyte progenitors increases miR-219a-5p expression and the number of mature cells. Overall, this study indicates that NGF inhibits oligodendrogenesis and myelination by down-regulating miR-219a-5p levels, suggesting a novel molecular circuitry that can be exploited for the discovery of new effectors for remyelination in human demyelinating diseases, such as Multiple Sclerosis.
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spelling pubmed-79200492021-03-02 Nerve Growth Factor Neutralization Promotes Oligodendrogenesis by Increasing miR-219a-5p Levels Brandi, Rossella Fabiano, Marietta Giorgi, Corinna Arisi, Ivan La Regina, Federico Malerba, Francesca Turturro, Sabrina Storti, Andrea Ennio Ricevuti, Flavia Amadio, Susanna Volontè, Cinzia Capsoni, Simona Scardigli, Raffaella D’Onofrio, Mara Cattaneo, Antonino Cells Article In the brain, the neurotrophin Nerve growth factor (NGF) regulates not only neuronal survival and differentiation, but also glial and microglial functions and neuroinflammation. NGF is known to regulate oligodendrogenesis, reducing myelination in the central nervous system (CNS). In this study, we found that NGF controls oligodendrogenesis by modulating the levels of miR-219a-5p, a well-known positive regulator of oligodendrocyte differentiation. We exploited an NGF-deprivation mouse model, the AD11 mice, in which the postnatal expression of an anti-NGF antibody leads to NGF neutralization and progressive neurodegeneration. Notably, we found that these mice also display increased myelination. A microRNA profiling of AD11 brain samples and qRT-PCR analyses revealed that NGF deprivation leads to an increase of miR-219a-5p levels in hippocampus and cortex and a corresponding down-regulation of its predicted targets. Neurospheres isolated from the hippocampus of AD11 mice give rise to more oligodendrocytes and this process is dependent on miR-219a-5p, as shown by decoy-mediated inhibition of this microRNA. Moreover, treatment of AD11 neurospheres with NGF inhibits miR-219a-5p up-regulation and, consequently, oligodendrocyte differentiation, while anti-NGF treatment of wild type (WT) oligodendrocyte progenitors increases miR-219a-5p expression and the number of mature cells. Overall, this study indicates that NGF inhibits oligodendrogenesis and myelination by down-regulating miR-219a-5p levels, suggesting a novel molecular circuitry that can be exploited for the discovery of new effectors for remyelination in human demyelinating diseases, such as Multiple Sclerosis. MDPI 2021-02-16 /pmc/articles/PMC7920049/ /pubmed/33669304 http://dx.doi.org/10.3390/cells10020405 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Brandi, Rossella
Fabiano, Marietta
Giorgi, Corinna
Arisi, Ivan
La Regina, Federico
Malerba, Francesca
Turturro, Sabrina
Storti, Andrea Ennio
Ricevuti, Flavia
Amadio, Susanna
Volontè, Cinzia
Capsoni, Simona
Scardigli, Raffaella
D’Onofrio, Mara
Cattaneo, Antonino
Nerve Growth Factor Neutralization Promotes Oligodendrogenesis by Increasing miR-219a-5p Levels
title Nerve Growth Factor Neutralization Promotes Oligodendrogenesis by Increasing miR-219a-5p Levels
title_full Nerve Growth Factor Neutralization Promotes Oligodendrogenesis by Increasing miR-219a-5p Levels
title_fullStr Nerve Growth Factor Neutralization Promotes Oligodendrogenesis by Increasing miR-219a-5p Levels
title_full_unstemmed Nerve Growth Factor Neutralization Promotes Oligodendrogenesis by Increasing miR-219a-5p Levels
title_short Nerve Growth Factor Neutralization Promotes Oligodendrogenesis by Increasing miR-219a-5p Levels
title_sort nerve growth factor neutralization promotes oligodendrogenesis by increasing mir-219a-5p levels
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920049/
https://www.ncbi.nlm.nih.gov/pubmed/33669304
http://dx.doi.org/10.3390/cells10020405
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