Interaction of Regulatory Factor X (RFX) factors and the mineralocorticoid receptor (MR) in neuronal differentiation and ciliogenesis in embryonic an

调节因子 X (RFX) 因子与盐皮质激素受体 (MR) 在胚胎神经元分化和纤毛发生中的相互作用

• 批准号: 2732436
• 金额: --
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2732436
• 关键词: Interaction; Regulatory; Factor; RFX; factors

Glucocorticoid hormones play very important functional roles in the body. They regulate metabolism, the immune system as well as many brain functions to maintain health and wellbeing. Dysregulation of glucocorticoid hormone function is known to enhance vulnerability for developing mental health disorders like major depression, anxiety and post-traumatic stress disorder. Presently, however, the molecular underpinnings of these glucocorticoid effects on the brain have still not been clarified. The brain structure mostly investigated is the hippocampus because of its role in stress coping and learning and memory processes. Glucocorticoid hormones act on the hippocampus through interaction with two intracellular receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), which act like ligand-dependent transcription factors. Recently, we conducted so-called chromatin immunoprecipitation (ChIP) analysis on the hippocampus to identify, for the first time, the genes with which MR and GR interact under baseline and stress conditions (see Mifsud & Reul (2016) Proc. Natl. Acad. Sci. USA 113:11336-41; Mifsud et al. (2021) Nature Communications 12: 4737). Amongst many findings, we discovered that, the MR in particular, is involved in neuronal differentiation and cilia function. Cilia are hair-like protrusions from cells, including neurons, that play critical roles in sensory and developmental processes. Both neuronal differentiation and ciliogenesis are part of the adult neurogenesis process taking place in the dentate gyrus, a highly plastic region of the hippocampus. Indeed, MR is thought to play a role in the neuronal differentiation phase of dentate neurogenesis but exactly how is presently unknown. We were able to confirm that MR is critical for neuronal differentiation and ciliogenesis in human foetal neuronal progenitor cells (hfNPCs; Mifsud et al., 2021). We also discovered that, most likely at the genome, MR interacts with so called Regulatory Factor X (RFX) factors, which are critical for ciliogenesis. These novel findings provide a solid rationale and basis for the in-depth investigation of the connection between MR and RFX factors in relation to neuronal differentiation and ciliogenesis as part of the embryonic and adult neurogenesis process.

糖皮质激素在机体中起着非常重要的功能作用。它们调节新陈代谢、免疫系统以及许多大脑功能，以维持健康和福祉。众所周知，糖皮质激素功能失调会增加患上严重抑郁症、焦虑症和创伤后应激障碍等心理健康疾病的可能性。然而，目前，这些糖皮质激素对大脑的影响的分子基础仍然没有得到澄清。研究最多的大脑结构是海马体，因为它在压力应对和学习记忆过程中发挥作用。糖皮质激素通过与两种细胞内受体（盐皮质激素受体（MR）和糖皮质激素受体（GR））相互作用作用而作用于海马，这两种受体的作用类似于配体依赖性转录因子。最近，我们对海马进行了所谓的染色质免疫沉淀（ChIP）分析，以首次鉴定在基线和应激条件下MR和GR相互作用的基因（参见Mifsud & Reul（2016）Proc. Natl. Acad. Sci. USA 113：11336-41; Mifsud等人（2021）Nature Communications 12：4737）。在众多的研究结果中，我们发现，特别是MR，参与神经元分化和纤毛功能。纤毛是细胞（包括神经元）的毛发状突起，在感觉和发育过程中起着关键作用。神经元分化和纤毛发生都是成年神经发生过程的一部分，发生在海马的高度可塑性区域齿状回。事实上，MR被认为在齿状神经发生的神经元分化阶段发挥作用，但目前尚不清楚确切的方式。我们能够证实MR对于人胎儿神经元祖细胞中的神经元分化和纤毛发生是关键的（hfNPC; Mifsud等人，2021年）。我们还发现，最有可能在基因组中，MR与所谓的调节因子X（RFX）因子相互作用，这对纤毛发生至关重要。这些新的研究结果提供了坚实的理论基础和深入调查的MR和RFX因素之间的联系，神经元分化和纤毛作为胚胎和成人神经发生过程的一部分。