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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Main Authors: Saad Omais, Rouba N. Hilal, Nour N. Halaby, Carine Jaafar, Noël Ghanem
Format: Article
Language:English
Published: Elsevier 2022-01-01
Series:Aging Brain
Subjects:
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.
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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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AT carinejaafar agingentailsdistinctrequirementsforrbatmaintainingadultneurogenesis
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