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Published on: March 20, 2014
Dexamethasone indirectly induces Ndrg2 expression in rat astrocytes
Kou Takahashi1, Akiyoshi Saitoh, Misa Yamada
1Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
Journal of Neuroscience Research
|September 20, 2011
Summary
Glucocorticoid treatment increases Ndrg2 gene expression in astrocytes indirectly. Nuclear factor-κB (NFκB) or paired box gene 5 (Pax5) binding sites, not GRE1/2, mediate this dexamethasone-induced Ndrg2 regulation.
Area of Science:
- Neuroscience
- Molecular Biology
- Endocrinology
Background:
- N-myc downstream-regulated gene 2 (Ndrg2) is implicated in cell functions and brain responses to stress.
- Glucocorticoid treatment or chronic stress induces Ndrg2 expression in the brain.
- Previous studies suggested glucocorticoid response elements (GREs) regulate Ndrg2 in astrocytes.
Purpose of the Study:
- To investigate the precise molecular mechanisms underlying dexamethasone-induced Ndrg2 expression in rat astrocytes.
- To determine the role of GREs and other regulatory elements in Ndrg2 gene induction.
Main Methods:
- Primary rat astrocytes were treated with dexamethasone and analyzed for Ndrg2 mRNA and protein levels.
- Glucocorticoid receptor antagonist (RU486) and protein synthesis inhibitor (cycloheximide) were used to assess receptor and protein synthesis involvement.
- Reporter assays with mutated promoter constructs identified key regulatory regions and transcription factor binding sites.
Main Results:
- Dexamethasone significantly increased Ndrg2 mRNA and protein in a dose-dependent manner, blocked by RU486.
- Dexamethasone-induced Ndrg2 expression was partially inhibited by cycloheximide, suggesting indirect regulation.
- Deletion of a putative GRE1/2 did not affect induction; however, a region containing NFκB and Pax5 binding sites was crucial.
- Mutating NFκB or Pax5 binding sites abolished dexamethasone-induced promoter activation, while Ebf1 site mutation had no effect.
Conclusions:
- Dexamethasone indirectly induces Ndrg2 expression in astrocytes at the transcriptional level.
- The induction is mediated by transcription factors NFκB and Pax5 binding to specific sites, not by GRE1/2.
- These findings reveal a novel regulatory pathway for Ndrg2 expression in response to glucocorticoids in the brain.
