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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2021.621076/full |
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| author | Loïc M. Cochard Loïc M. Cochard Louis-Charles Levros Louis-Charles Levros Sandra E. Joppé Sandra E. Joppé Federico Pratesi Federico Pratesi Anne Aumont Anne Aumont Karl J. L. Fernandes Karl J. L. Fernandes |
| author_facet | Loïc M. Cochard Loïc M. Cochard Louis-Charles Levros Louis-Charles Levros Sandra E. Joppé Sandra E. Joppé Federico Pratesi Federico Pratesi Anne Aumont Anne Aumont Karl J. L. Fernandes Karl J. L. Fernandes |
| author_sort | Loïc M. Cochard |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-13T18:59:26Z |
| format | Article |
| id | doaj.art-2c298c0b1ab64c679124a8c30c68d8a4 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-13T18:59:26Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neuroscience |
| spelling | doaj.art-2c298c0b1ab64c679124a8c30c68d8a42022-12-21T23:34:43ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2021-03-011510.3389/fnins.2021.621076621076Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse ForebrainLoïc M. Cochard0Loïc M. Cochard1Louis-Charles Levros2Louis-Charles Levros3Sandra E. Joppé4Sandra E. Joppé5Federico Pratesi6Federico Pratesi7Anne Aumont8Anne Aumont9Karl J. L. Fernandes10Karl J. L. Fernandes11University of Montreal Hospital Research Centre (CRCHUM), Montreal, QC, CanadaDepartment of Neurosciences, Faculty of Medicine, Université de Montreal, Montreal, QC, CanadaUniversity of Montreal Hospital Research Centre (CRCHUM), Montreal, QC, CanadaDepartment of Neurosciences, Faculty of Medicine, Université de Montreal, Montreal, QC, CanadaUniversity of Montreal Hospital Research Centre (CRCHUM), Montreal, QC, CanadaDepartment of Neurosciences, Faculty of Medicine, Université de Montreal, Montreal, QC, CanadaUniversity of Montreal Hospital Research Centre (CRCHUM), Montreal, QC, CanadaDepartment of Neurosciences, Faculty of Medicine, Université de Montreal, Montreal, QC, CanadaUniversity of Montreal Hospital Research Centre (CRCHUM), Montreal, QC, CanadaDepartment of Neurosciences, Faculty of Medicine, Université de Montreal, Montreal, QC, CanadaUniversity of Montreal Hospital Research Centre (CRCHUM), Montreal, QC, CanadaDepartment of Neurosciences, Faculty of Medicine, Université de Montreal, Montreal, QC, CanadaThe 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.https://www.frontiersin.org/articles/10.3389/fnins.2021.621076/fullepidermal growth factorneural stem cellagingAlzheimer’s diseaseneurogenesisquiescence |
| spellingShingle | Loïc M. Cochard Loïc M. Cochard Louis-Charles Levros Louis-Charles Levros Sandra E. Joppé Sandra E. Joppé Federico Pratesi Federico Pratesi Anne Aumont Anne Aumont Karl J. L. Fernandes Karl J. L. Fernandes Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain Frontiers in Neuroscience epidermal growth factor neural stem cell aging Alzheimer’s disease neurogenesis quiescence |
| 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 | epidermal growth factor neural stem cell aging Alzheimer’s disease neurogenesis quiescence |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2021.621076/full |
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