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Nurr1 protein is required for N-Methyl-d-aspartic Acid (NMDA) receptor-mediated neuronal survival
Barneda Zahonero, Bruna (Universitat Autònoma de Barcelona. Institut de Neurociències)
Servitja i Duque, Joan-Marc (Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))
Badiola Benito, Nahuai (Universitat Autònoma de Barcelona. Institut de Neurociències)
Miñano Molina, Alfredo Jesús (Universitat Autònoma de Barcelona. Institut de Neurociències)
Fadó Andrés, Rut (Universitat Autònoma de Barcelona. Institut de Neurociències)
Saura Antolín, Carlos A. (Carlos Alberto) (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)
Rodríguez Álvarez, José (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)

Date: 2012
Abstract: NMDA receptor (NMDAR) stimulation promotes neuronal survival during brain development. Cerebellar granule cells (CGCs) need NMDAR stimulation to survive and develop. These neurons differentiate and mature during its migration from the external granular layer to the internal granular layer, and lack of excitatory inputs triggers their apoptotic death. It is possible to mimic this process in vitro by culturing CGCs in low KCl concentrations (5 mm) in the presence or absence of NMDA. Using this experimental approach, we have obtained whole genome expression profiles after 3 and 8 h of NMDA addition to identify genes involved in NMDA-mediated survival of CGCs. One of the identified genes was Nurr1, a member of the orphan nuclear receptor subfamily Nr4a. Our results report a direct regulation of Nurr1 by CREB after NMDAR stimulation. ChIP assay confirmed CREB binding to Nurr1 promoter, whereas CREB shRNA blocked NMDA-mediated increase in Nurr1 expression. Moreover, we show that Nurr1 is important for NMDAR survival effect. We show that Nurr1 binds to Bdnf promoter IV and that silencing Nurr1 by shRNA leads to a decrease in brain-derived neurotrophic factor (BDNF) protein levels and a reduction of NMDA neuroprotective effect. Also, we report that Nurr1 and BDNF show a similar expression pattern during postnatal cerebellar development. Thus, we conclude that Nurr1 is a downstream target of CREB and that it is responsible for the NMDA-mediated increase in BDNF, which is necessary for the NMDA-mediated prosurvival effect on neurons.
Note: Número d'acord de subvenció MICINN/SAF2008-01904
Note: Número d'acord de subvenció MICINN/SAF2011-30281
Note: Número d'acord de subvenció MICINN/SAF010-20925
Note: Número d'acord de subvenció CIBERNED/CB06/05/0042
Rights: Tots els drets reservats.
Language: Anglès.
Document: article ; recerca ; publishedVersion
Subject: Brain-derived neurotrophic factor (BDNF) ; Cerebellum ; CREB ; Glutamate receptors ionotropic (AMPA, NMDA) ; Neurodevelopment ; Cerebellar granule neurons ; Nurr1
Published in: The Journal of biological chemistry, Vol. 287, No. 14 (2012) , p. 11351-11362, ISSN 0021-9258

DOI: 10.1074/jbc.M111.272427
PMID: 22294685


32 p, 2.5 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (scientific output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles

 Record created 2017-03-21, last modified 2019-05-23



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