期刊
ENDOCRINOLOGY
卷 153, 期 11, 页码 5334-5345出版社
ENDOCRINE SOC
DOI: 10.1210/en.2012-1303
关键词
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资金
- National Institute of Neurological Disorders and Stroke
- National Institutes of Health [1 R01 NS046690]
- National Science Foundation [IOS 0922583]
- National Institute of Diabetes and Digestive Kidney Diseases [NIHP60 DK20572]
- Rackham Graduate School
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan
- National Institutes of Health Cellular and Molecular Biology Training Grant at the University of Michigan [T32-GM007315]
- Division Of Integrative Organismal Systems
- Direct For Biological Sciences [0922583] Funding Source: National Science Foundation
Stress has complex effects on hippocampal structure and function, which consequently affects learning and memory. These effects are mediated in part by circulating glucocorticoids (GC) acting via the intracellular GC receptor (GR) and mineralocorticoid receptor (MR). Here, we investigated GC regulation of Kruppel-like factor 9 (KLF9), a transcription factor implicated in neuronal development and plasticity. Injection of corticosterone (CORT) in postnatal d6 and 30 mice increased Klf9 mRNA and heteronuclear RNA by 1 h in the hippocampal region. Treatment of the mouse hippocampal cell line HT-22 with CORT caused a time-and dose-dependent increase in Klf9 mRNA. The CORT induction of Klf9 was resistant to protein synthesis inhibition, suggesting that Klf9 is a direct CORT-response gene. In support of this hypothesis, we identified two GR/MR response elements (GRE/MRE) located -6.1 and -5.3 kb relative to the transcription start site, and we verified their functionality by enhancer-reporter, gel shift, and chromatin immunoprecipitation assays. The -5.3-kb GRE/MRE is largely conserved across tetrapods, but conserved orthologs of the -6.1-kb GRE/MRE were only detected in therian mammals. GC treatment caused recruitment of the GR, histone hyperacetylation, and nucleosome removal at Klf9 upstream regions. Our findings support a predominant role for GR, with a minor contribution of MR, in the direct regulation of Klf9 acting via two GRE/MRE located in the 5'-flanking region of the gene. KLF9 may play a key role in GC actions on hippocampal development and plasticity. (Endocrinology 153:5334-5345, 2012)
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