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Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain

The ventricular-subventricular zone (V-SVZ) is the principal neurogenic niche in the adult mammalian forebrain. Neural stem/progenitor cell (NSPC) activity within the V-SVZ is controlled by numerous of extrinsic factors, whose downstream effects on NSPC proliferation, survival and differentiation ar...

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Autores principales: Cochard, Loïc M., Levros, Louis-Charles, Joppé, Sandra E., Pratesi, Federico, Aumont, Anne, Fernandes, Karl J. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032885/
https://www.ncbi.nlm.nih.gov/pubmed/33841077
http://dx.doi.org/10.3389/fnins.2021.621076
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author Cochard, Loïc M.
Levros, Louis-Charles
Joppé, Sandra E.
Pratesi, Federico
Aumont, Anne
Fernandes, Karl J. L.
author_facet Cochard, Loïc M.
Levros, Louis-Charles
Joppé, Sandra E.
Pratesi, Federico
Aumont, Anne
Fernandes, Karl J. L.
author_sort Cochard, Loïc M.
collection PubMed
description The ventricular-subventricular zone (V-SVZ) is the principal neurogenic niche in the adult mammalian forebrain. Neural stem/progenitor cell (NSPC) activity within the V-SVZ is controlled by numerous of extrinsic factors, whose downstream effects on NSPC proliferation, survival and differentiation are transduced via a limited number of intracellular signaling pathways. Here, we investigated the relationship between age-related changes in NSPC output and activity of signaling pathways downstream of the epidermal growth factor receptor (EGFR), a major regulator of NSPC activity. Biochemical experiments indicated that age-related decline of NSPC activity in vivo is accompanied by selective deficits amongst various EGFR-induced signal pathways within the V-SVZ niche. Pharmacological loss-of-function signaling experiments with cultured NSPCs revealed both overlap and selectivity in the biological functions modulated by the EGFR-induced PI3K/AKT, MEK/ERK and mTOR signaling modules. Specifically, while all three modules promoted EGFR-mediated NSPC proliferation, only mTOR contributed to NSPC survival and only MEK/ERK repressed NSPC differentiation. Using a gain-of-function in vivo genetic approach, we electroporated a constitutively active EGFR construct into a subpopulation of quiescent, EGFR-negative neural stem cells (qNSCs); this ectopic activation of EGFR signaling enabled qNSCs to divide in 3-month-old early adult mice, but not in mice at middle-age or carrying familial Alzheimer disease mutations. Thus, (i) individual EGFR-induced signaling pathways have dissociable effects on NSPC proliferation, survival, and differentiation, (ii) activation of EGFR signaling is sufficient to stimulate qNSC cell cycle entry during early adulthood, and (iii) the proliferative effects of EGFR-induced signaling are dominantly overridden by anti-proliferative signals associated with aging and Alzheimer’s disease.
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spelling pubmed-80328852021-04-10 Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain Cochard, Loïc M. Levros, Louis-Charles Joppé, Sandra E. Pratesi, Federico Aumont, Anne Fernandes, Karl J. L. Front Neurosci Neuroscience The ventricular-subventricular zone (V-SVZ) is the principal neurogenic niche in the adult mammalian forebrain. Neural stem/progenitor cell (NSPC) activity within the V-SVZ is controlled by numerous of extrinsic factors, whose downstream effects on NSPC proliferation, survival and differentiation are transduced via a limited number of intracellular signaling pathways. Here, we investigated the relationship between age-related changes in NSPC output and activity of signaling pathways downstream of the epidermal growth factor receptor (EGFR), a major regulator of NSPC activity. Biochemical experiments indicated that age-related decline of NSPC activity in vivo is accompanied by selective deficits amongst various EGFR-induced signal pathways within the V-SVZ niche. Pharmacological loss-of-function signaling experiments with cultured NSPCs revealed both overlap and selectivity in the biological functions modulated by the EGFR-induced PI3K/AKT, MEK/ERK and mTOR signaling modules. Specifically, while all three modules promoted EGFR-mediated NSPC proliferation, only mTOR contributed to NSPC survival and only MEK/ERK repressed NSPC differentiation. Using a gain-of-function in vivo genetic approach, we electroporated a constitutively active EGFR construct into a subpopulation of quiescent, EGFR-negative neural stem cells (qNSCs); this ectopic activation of EGFR signaling enabled qNSCs to divide in 3-month-old early adult mice, but not in mice at middle-age or carrying familial Alzheimer disease mutations. Thus, (i) individual EGFR-induced signaling pathways have dissociable effects on NSPC proliferation, survival, and differentiation, (ii) activation of EGFR signaling is sufficient to stimulate qNSC cell cycle entry during early adulthood, and (iii) the proliferative effects of EGFR-induced signaling are dominantly overridden by anti-proliferative signals associated with aging and Alzheimer’s disease. Frontiers Media S.A. 2021-03-26 /pmc/articles/PMC8032885/ /pubmed/33841077 http://dx.doi.org/10.3389/fnins.2021.621076 Text en Copyright © 2021 Cochard, Levros, Joppé, Pratesi, Aumont and Fernandes. https://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 Neuroscience
Cochard, Loïc M.
Levros, Louis-Charles
Joppé, Sandra E.
Pratesi, Federico
Aumont, Anne
Fernandes, Karl J. L.
Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain
title Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain
title_full Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain
title_fullStr Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain
title_full_unstemmed Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain
title_short Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain
title_sort manipulation of egfr-induced signaling for the recruitment of quiescent neural stem cells in the adult mouse forebrain
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032885/
https://www.ncbi.nlm.nih.gov/pubmed/33841077
http://dx.doi.org/10.3389/fnins.2021.621076
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