Transcriptional suppression of the neuronal PAS domain 4 (Npas4) gene by stress via the binding of agonist-bound glucocorticoid receptor to its promoter.

Neuronal PAS domain 4 (NPAS4), a brain-specific helix-loop-helix transcription factor, has recently been shown to regulate the development of GABAergic inhibitory neurons. We previously reported that Npas4 mRNA expression levels were reduced in the hippocampus of mice exposed to social isolation or restraint stress, which was accompanied by impairment of memory, emotional behavior, and hippocampal neurogenesis. Therefore, the reduction of NPAS4 expression may play a role in stress-induced brain dysfunction. In this study, to investigate the transcriptional regulation of Npas4 by stress, we focused on the effect of glucocorticoids (GCs) upon Npas4 transcription. Corticosterone treatment reduced Npas4 expression in the frontal cortex and hippocampus, whereas adrenalectomy caused an increase in expression. GC receptor (GR) antagonist, mifepristone, inhibited the stress-induced reduction of Npas4 expression. Putative negative glucocorticoid response elements (GREs) were found -2000 to -1000 upstream of the Npas4 transcription initiation site. Npas4 promoter activity was increased by mifepristone or by mutation of the negative GRE sequences. A chromatin immunoprecipitation assay revealed that restraint stress increased the binding of GR to Npas4 promoter region in the hippocampus. These results suggest that transcription of Npas4 is down-regulated by stress via the binding of agonist-bound GR to its promoter.

Furukawa-Hibi Y ，Yun J ，Nagai T ，Yamada K ... -  《-》

Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4.

Neurogenesis in the hippocampus occurs throughout life in a wide range of species and could be associated with hippocampus-dependent learning and memory. Stress is well established to seriously perturb physiological/psychological homeostasis and affect hippocampal function. In the present study, to investigate the effect of chronic restraint stress in early life on hippocampal neurogenesis and hippocampus-dependent memory, 3-week-old mice were subjected to restraint stress 6 days a week for 4 weeks. The chronic restraint stress significantly decreased the hippocampal volume by 6.3% and impaired hippocampal neurogenesis as indicated by the reduced number of Ki67-, 5-bromo-2'-deoxyuridine- and doublecortin-positive cells in the dentate gyrus. The chronic restraint stress severely impaired hippocampus-dependent contextual fear memory without affecting hippocampus-independent fear memory. The expression level of brain-specific transcription factor neuronal PAS domain protein 4 (Npas4) mRNA in the hippocampus was down-regulated by the restraint stress or by acute corticosterone treatment. Npas4 immunoreactivity was detected in progenitors, immature and mature neurons of the dentate gyrus in control and stressed mice. Our findings suggest that the chronic restraint stress decreases hippocampal neurogenesis, leading to an impairment of hippocampus-dependent fear memory in mice. Corticosterone-induced down-regulation of Npas4 expression may play a role in stress-induced impairment of hippocampal function.

Yun J ，Koike H ，Ibi D ，Toth E ，Mizoguchi H ，Nitta A ，Yoneyama M ，Ogita K ，Yoneda Y ，Nabeshima T ，Nagai T ，Yamada K ... -  《-》

Stress increases DNA methylation of the neuronal PAS domain 4 (Npas4) gene.

Furukawa-Hibi Y ，Nagai T ，Yun J ，Yamada K ... -  《-》

Npas4, a novel helix-loop-helix PAS domain protein, is regulated in response to cerebral ischemia.

Shamloo M ，Soriano L ，von Schack D ，Rickhag M ，Chin DJ ，Gonzalez-Zulueta M ，Gido G ，Urfer R ，Wieloch T ，Nikolich K ... -  《-》

Autoregulation of human relaxin-2 gene expression critically involves relaxin and glucocorticoid receptor binding to glucocorticoid response half-sites in the relaxin-2 promoter.

Dschietzig T ，Bartsch C ，Wessler S ，Baumann G ，Stangl K ... -  《-》