Loss of postnatal quiescence of neural stem cells through mTOR activation upon genetic removal of cysteine string protein-α
Neural stem cells continuously generate newborn neurons that integrate into and modify neural circuitry in the adult hippocampus. The molecular mechanisms that regulate or perturb neural stem cell proliferation and differentiation, however, remain poorly understood. Here, we have found that mouse hippocampal radial glia-like (RGL) neural stem cells express the synaptic cochaperone cysteine string protein-α (CSP-α). Remarkably, in CSP-α knockout mice, RGL stem cells lose quiescence postnatally and enter into a high-proliferation regime that increases the production of neural intermediate progenitor cells, thereby exhausting the hippocampal neural stem cell pool. In cell culture, stem cells in hippocampal neurospheres display alterations in proliferation for which hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway is the primary cause of neurogenesis deregulation in the absence of CSP-α. In addition, RGL cells lose quiescence upon specific conditional targeting of CSP-α in adult neural stem cells. Our findings demonstrate an unanticipated cell-autonomic and circuit-independent disruption of postnatal neurogenesis in the absence of CSP-α and highlight a direct or indirect CSP-α/mTOR signaling interaction that may underlie molecular mechanisms of brain dysfunction and neurodegeneration.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:116 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 116(2019), 16 vom: 16. Apr., Seite 8000-8009 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nieto-González, Jose L [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 23.03.2020 Date Revised 04.12.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.1817183116 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM295487674 |
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| 100 | 1 | |a Nieto-González, Jose L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Loss of postnatal quiescence of neural stem cells through mTOR activation upon genetic removal of cysteine string protein-α |
| 264 | 1 | |c 2019 | |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Neural stem cells continuously generate newborn neurons that integrate into and modify neural circuitry in the adult hippocampus. The molecular mechanisms that regulate or perturb neural stem cell proliferation and differentiation, however, remain poorly understood. Here, we have found that mouse hippocampal radial glia-like (RGL) neural stem cells express the synaptic cochaperone cysteine string protein-α (CSP-α). Remarkably, in CSP-α knockout mice, RGL stem cells lose quiescence postnatally and enter into a high-proliferation regime that increases the production of neural intermediate progenitor cells, thereby exhausting the hippocampal neural stem cell pool. In cell culture, stem cells in hippocampal neurospheres display alterations in proliferation for which hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway is the primary cause of neurogenesis deregulation in the absence of CSP-α. In addition, RGL cells lose quiescence upon specific conditional targeting of CSP-α in adult neural stem cells. Our findings demonstrate an unanticipated cell-autonomic and circuit-independent disruption of postnatal neurogenesis in the absence of CSP-α and highlight a direct or indirect CSP-α/mTOR signaling interaction that may underlie molecular mechanisms of brain dysfunction and neurodegeneration | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a DNAJC5 | |
| 650 | 4 | |a adult neurogenesis | |
| 650 | 4 | |a adult-onset neuronal ceroid lipofuscinosis | |
| 650 | 4 | |a lysosome | |
| 650 | 4 | |a synaptic neurodegeneration | |
| 650 | 7 | |a HSP40 Heat-Shock Proteins |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a cysteine string protein |2 NLM | |
| 650 | 7 | |a mTOR protein, mouse |2 NLM | |
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| 650 | 7 | |a TOR Serine-Threonine Kinases |2 NLM | |
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| 700 | 1 | |a Gómez-Sánchez, Leonardo |e verfasserin |4 aut | |
| 700 | 1 | |a Mavillard, Fabiola |e verfasserin |4 aut | |
| 700 | 1 | |a Linares-Clemente, Pedro |e verfasserin |4 aut | |
| 700 | 1 | |a Rivero, María C |e verfasserin |4 aut | |
| 700 | 1 | |a Valenzuela-Villatoro, Marina |e verfasserin |4 aut | |
| 700 | 1 | |a Muñoz-Bravo, José L |e verfasserin |4 aut | |
| 700 | 1 | |a Pardal, Ricardo |e verfasserin |4 aut | |
| 700 | 1 | |a Fernández-Chacón, Rafael |e verfasserin |4 aut | |
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