Aging entails distinct requirements for Rb at maintaining adult neurogenesis
Cell cycle proteins play essential roles in regulating embryonic and adult neurogenesis in the mammalian brain. A key example is the Retinoblastoma protein (Rb) whose loss disrupts the whole neurogenic program during brain development, but only results in increased progenitor proliferation in the ad...
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Format: | Article |
Language: | English |
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Elsevier
2022-01-01
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Series: | Aging Brain |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2589958922000135 |
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author | Saad Omais Rouba N. Hilal Nour N. Halaby Carine Jaafar Noël Ghanem |
author_facet | Saad Omais Rouba N. Hilal Nour N. Halaby Carine Jaafar Noël Ghanem |
author_sort | Saad Omais |
collection | DOAJ |
description | Cell cycle proteins play essential roles in regulating embryonic and adult neurogenesis in the mammalian brain. A key example is the Retinoblastoma protein (Rb) whose loss disrupts the whole neurogenic program during brain development, but only results in increased progenitor proliferation in the adult subventricular zone (SVZ) and compromised long-term neuronal survival in the adult olfactory bulb (OB). Whether this holds true of neurogenesis in the aged brain remains unknown. In this study, we find no evidence of irregular proliferation or early commitment defects in the mid-aged (12-month-old) and old-aged (20-month-old) SVZ following tamoxifen-inducible Rb knockout (Rb iKO) in mice. However, we highlight a striking defect in early maturation of Rb-deficient migrating neuroblasts along the rostral migratory stream (RMS), followed by massive decline in neuronal generation inside the aged OB. In the absence of Rb, we also show evidence of incomplete cell cycle re-entry (CCE) along with DNA damage in the young OB, while we find a similar trend towards CCE but no clear signs of DNA damage or neurodegenerative signatures (pTau or Synuclein accumulation) in the aged OB. However, such phenotype could be masked by the severe maturation defect reported above in addition to the natural decline in adult neurogenesis with age. Overall, we show that Rb is required to prevent CCE and DNA damage in adult-born OB neurons, hence maintain neuronal survival. Moreover, while loss of Rb alone is insufficient to trigger seeding of neurotoxic species, this study reveals age-dependent non-monotonic dynamics in regulating neurogenesis by Rb. |
first_indexed | 2024-04-13T05:42:22Z |
format | Article |
id | doaj.art-8658cb7090824daaa51bcb3920973ca4 |
institution | Directory Open Access Journal |
issn | 2589-9589 |
language | English |
last_indexed | 2024-04-13T05:42:22Z |
publishDate | 2022-01-01 |
publisher | Elsevier |
record_format | Article |
series | Aging Brain |
spelling | doaj.art-8658cb7090824daaa51bcb3920973ca42022-12-22T03:00:04ZengElsevierAging Brain2589-95892022-01-012100041Aging entails distinct requirements for Rb at maintaining adult neurogenesisSaad Omais0Rouba N. Hilal1Nour N. Halaby2Carine Jaafar3Noël Ghanem4Department of Biology, American University of Beirut, LebanonDepartment of Biology, American University of Beirut, LebanonDepartment of Biology, American University of Beirut, LebanonDepartment of Biology, American University of Beirut, LebanonCorresponding author at: Associate Professor, Department of Biology, American University of Beirut, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon.; Department of Biology, American University of Beirut, LebanonCell cycle proteins play essential roles in regulating embryonic and adult neurogenesis in the mammalian brain. A key example is the Retinoblastoma protein (Rb) whose loss disrupts the whole neurogenic program during brain development, but only results in increased progenitor proliferation in the adult subventricular zone (SVZ) and compromised long-term neuronal survival in the adult olfactory bulb (OB). Whether this holds true of neurogenesis in the aged brain remains unknown. In this study, we find no evidence of irregular proliferation or early commitment defects in the mid-aged (12-month-old) and old-aged (20-month-old) SVZ following tamoxifen-inducible Rb knockout (Rb iKO) in mice. However, we highlight a striking defect in early maturation of Rb-deficient migrating neuroblasts along the rostral migratory stream (RMS), followed by massive decline in neuronal generation inside the aged OB. In the absence of Rb, we also show evidence of incomplete cell cycle re-entry (CCE) along with DNA damage in the young OB, while we find a similar trend towards CCE but no clear signs of DNA damage or neurodegenerative signatures (pTau or Synuclein accumulation) in the aged OB. However, such phenotype could be masked by the severe maturation defect reported above in addition to the natural decline in adult neurogenesis with age. Overall, we show that Rb is required to prevent CCE and DNA damage in adult-born OB neurons, hence maintain neuronal survival. Moreover, while loss of Rb alone is insufficient to trigger seeding of neurotoxic species, this study reveals age-dependent non-monotonic dynamics in regulating neurogenesis by Rb.http://www.sciencedirect.com/science/article/pii/S2589958922000135Aging brainRbAdult neurogenesisSubventricular zone – olfactory bulbNestinCreERT2 mice |
spellingShingle | Saad Omais Rouba N. Hilal Nour N. Halaby Carine Jaafar Noël Ghanem Aging entails distinct requirements for Rb at maintaining adult neurogenesis Aging Brain Aging brain Rb Adult neurogenesis Subventricular zone – olfactory bulb NestinCreERT2 mice |
title | Aging entails distinct requirements for Rb at maintaining adult neurogenesis |
title_full | Aging entails distinct requirements for Rb at maintaining adult neurogenesis |
title_fullStr | Aging entails distinct requirements for Rb at maintaining adult neurogenesis |
title_full_unstemmed | Aging entails distinct requirements for Rb at maintaining adult neurogenesis |
title_short | Aging entails distinct requirements for Rb at maintaining adult neurogenesis |
title_sort | aging entails distinct requirements for rb at maintaining adult neurogenesis |
topic | Aging brain Rb Adult neurogenesis Subventricular zone – olfactory bulb NestinCreERT2 mice |
url | http://www.sciencedirect.com/science/article/pii/S2589958922000135 |
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