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.

糖皮质激素在体内发挥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罹患重性抑郁、焦虑和创伤后应激障碍等精神健康疾病的风险。然而目前，这些糖皮质激素对大脑作用的分子基础尚未阐明。主要研究的大脑结构是海马体，因为它在压力应对以及学习和记忆过程中发挥着作用。糖皮质激素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，我们对海马体进行了所谓的染色质免疫沉淀 (ChIP) 分析，首次确定了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科学美国 113：11336-41；Mifsud 等（2021）自然通讯 12：4737。在众多发现中，我们发现，尤其是 MR，与神经元分化和纤毛功能有关。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发挥着关键作用。神经元分化和纤毛发生都是发生在齿状回（海马体的高度可塑性区域）中的成人神经发生过程的一部分。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，但具体如何发挥作用目前尚不清楚。我们能够证实 MR 对于人类胎儿神经元祖细胞的神经元分化和纤毛发生至关重要（hfNPC；Mifsud 等人，2021）。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，这对于纤毛发生至关重要。这些新发现为深入研究 MR 和 RFX 因子与神经元分化和纤毛发生（胚胎和成人神经发生过程的一部分）之间的联系提供了坚实的理论基础和基础。