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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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Autores principales: Omais, Saad, Hilal, Rouba N., Halaby, Nour N., Jaafar, Carine, Ghanem, Noël
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9997174/
https://www.ncbi.nlm.nih.gov/pubmed/36908894
http://dx.doi.org/10.1016/j.nbas.2022.100041
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author Omais, Saad
Hilal, Rouba N.
Halaby, Nour N.
Jaafar, Carine
Ghanem, Noël
author_facet Omais, Saad
Hilal, Rouba N.
Halaby, Nour N.
Jaafar, Carine
Ghanem, Noël
author_sort Omais, Saad
collection PubMed
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 pubmed-99971742023-03-09 Aging entails distinct requirements for Rb at maintaining adult neurogenesis Omais, Saad Hilal, Rouba N. Halaby, Nour N. Jaafar, Carine Ghanem, Noël Aging Brain Article 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. Elsevier 2022-05-11 /pmc/articles/PMC9997174/ /pubmed/36908894 http://dx.doi.org/10.1016/j.nbas.2022.100041 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Omais, Saad
Hilal, Rouba N.
Halaby, Nour N.
Jaafar, Carine
Ghanem, Noël
Aging entails distinct requirements for Rb at maintaining adult neurogenesis
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9997174/
https://www.ncbi.nlm.nih.gov/pubmed/36908894
http://dx.doi.org/10.1016/j.nbas.2022.100041
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