Nuclear factor of activated T-cells isoform c4 (NFATc4/NFAT3) as a mediator of antiapoptotic transcription in NMDA receptor-stimulated cortical neurons.
J Neurosci
; 29(48): 15331-40, 2009 Dec 02.
Article
em En
| MEDLINE
| ID: mdl-19955386
ABSTRACT
During cortical development, when NR2B subunit is the major component of the NMDA glutamate receptors (NMDARs), moderate NMDAR activity supports neuronal survival at least in part by regulating gene transcription. We report that, in cultured cortical neurons from newborn rats, the NMDARs activated the calcium-responsive transcription regulator nuclear factor of activated T cells (NFAT). Moreover, in developing rat cortex, the NFAT isoforms c3 and c4 (NFATc3 and NFATc4) were expressed at relatively higher levels at postnatal day 7 (P7) than P21, overlapping with the period of NMDAR-dependent survival. In cultured cortical neurons, NFATc3 and NFATc4 were regulated at least in part by the NR2B NMDAR. Conversely, knockdown of NFATc4 but not NFATc3 induced cortical neuron apoptosis. Likewise, NFATc4 inhibition prevented antiapoptotic neuroprotection in response to exogenous NMDA. Expression of the brain-derived neurotrophic factor (BDNF) was reduced by NFATc4 inhibition. NFATc4 regulated transcription by the NMDAR-responsive bdnf promoter IV. In addition, NMDAR blockers including NR2B-selective once reduced BDNF expression in P7 cortex and cultured cortical neurons. Finally, exogenous BDNF rescued from the proapoptotic effects of NFATc4 inhibition. These results identify bdnf as one of the target genes for the antiapoptotic signaling by NMDAR-NFATc4. Thus, the previously unrecognized NMDAR-NFATc4-BDNF pathway contributes to the survival signaling network that supports cortical development.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Córtex Cerebral
/
Apoptose
/
Receptores de N-Metil-D-Aspartato
/
Fatores de Transcrição NFATC
/
Neurônios
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Neurosci
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos