Department of Medicine, Division of Endocrinology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Department of Cognitive Neuroscience, Radboudumc, 6525 GA Nijmegen, The Netherlands.
Int J Mol Sci. 2019 Mar 29;20(7):1575. doi: 10.3390/ijms20071575.
Mineralocorticoid receptor (MR)-mediated signaling in the brain has been suggested as a protective factor in the development of psychopathology, in particular mood disorders. We recently identified genomic loci at which either MR or the closely related glucocorticoid receptor (GR) binds selectively, and found members of the NeuroD transcription factor family to be specifically associated with MR-bound DNA in the rat hippocampus. We show here using forebrain-specific MR knockout mice that GR binding to MR/GR joint target loci is not affected in any major way in the absence of MR. Neurod2 binding was also independent of MR binding. Moreover, functional comparison with MyoD family members indicates that it is the chromatin remodeling aspect of NeuroD, rather than its direct stimulation of transcription, that is responsible for potentiation of MR-mediated transcription. These findings suggest that NeuroD acts in a permissive way to enhance MR-mediated transcription, and they argue against competition for DNA binding as a mechanism of MR- over GR-specific binding.
矿物质皮质激素受体（MR）在大脑中的信号转导被认为是精神病理学，特别是情绪障碍发展中的一种保护因素。我们最近鉴定了 MR 或密切相关的糖皮质激素受体（GR）选择性结合的基因组位点，并发现神经源性转录因子家族的成员与大鼠海马体中 MR 结合的 DNA 特异性相关。我们在这里使用大脑特异性 MR 敲除小鼠表明，在没有 MR 的情况下，GR 结合到 MR/GR 联合靶位的方式没有受到任何重大影响。Neurod2 结合也与 MR 结合无关。此外，与 MyoD 家族成员的功能比较表明，NeuroD 增强 MR 介导的转录的作用是其染色质重塑方面，而不是其直接刺激转录，这负责增强 MR 介导的转录。这些发现表明，NeuroD 以允许的方式作用，以增强 MR 介导的转录，并且它们反对 DNA 结合的竞争作为 MR 特异性结合的机制。
