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Title: Transcription factor NRF2 controls the fate of neural stem cells in the subgranular zone of the hippocampus
Authors: Robledinos-Antón, Natalia
Rojo, Ana I
Ferreiro, Elisabete 
Núñez, Ángel
Krause, Karl-Heinz
Jaquet, Vincent
Cuadrado, Antonio
Keywords: Hippocampal neurogenesis; Aging; NRF2; Neural stem cells; Subgranular zone; Oxidative stress
Issue Date: Oct-2017
Publisher: Elsevier
Project: This work was funded by Grant SAF2016-76520-R of the Spanish Ministry of Economy and Competitiveness. NRA is recipient of a FPU contract of Spanish Ministry of Education Culture and Sports. EF is a recipient a postdoctoral fellowship: SFRH/BPD/86551/2012 (Financiado por Fundos FEDER através do Programa Operacional Factores de Competitividade – COMPETE 2020 e por Fundos Nacionais através da FCT –Fundação para a Ciência e a Tecnologia no âmbito do projecto Estratégico com referência atribuida pelo COMPETE: POCI-01- 0145-FEDER-007440). EF enjoyed a short term stay visit at AC's laboratory founded by COST action BM1402 MouseAge. 
Serial title, monograph or event: Redox Biology
Volume: 13
Abstract: Neural stem/progenitor cells (NSPCs) located at the subgranular zone (SGZ) of the hippocampus participate in the maintenance of synaptic networks that ensure cognitive functions during life. Although it is known that this neurogenic niche losses activity with oxidative stress and ageing, the molecular events involved in its regulation are largely unknown. Here, we studied the role of transcription factor Nuclear Factor-Erythroid 2-Related Factor 2 (NRF2) in the control of NSPCs destinies in the SGZ. We first describe that NRF2-knockout (Nrf2-/-) mice exhibit impaired long term potentiation, a function that requires integrity of the SGZ, therefore suggesting a cognitive deficit that might be linked to hippocampal neurogenesis. Then, we found a reduction in NSCs from birth to adulthood that was exacerbated in Nrf2-/- vs. Nrf2+/+ mice. The clonogenic and proliferative capacity of SGZ-derived NSPCs from newborn and 3-month-old Nrf2-/- mice was severely reduced as determined in neurosphere cultures. Nrf2-deficiency also impaired neuronal differentiation both the SGZ, and in neurosphere differentiation assays, leading to an abnormal production of astrocytes and oligodendrocytes vs. neurons. Rescue of Nrf2-/- NSPCs by ectopic expression of NRF2 attenuated the alterations in clonogenic, proliferative and differentiating capacity of hippocampal NSPCs. In turn, knockdown of the NRF2 gene in wild type NSPCs reproduced the data obtained with Nrf2-/- NSPCs. Our findings demonstrate the importance of NRF2 in the maintenance of proper proliferation and differentiation rates of hippocampal NSPCs and suggest that interventions to up-regulate NRF2 might provide a mechanism to preserve the neurogenic functionality of the hippocampus.
ISSN: 22132317
DOI: 10.1016/j.redox.2017.06.010
Rights: openAccess
Appears in Collections:IIIUC - Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais

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