THE MECHANISM AND SIGNIFICANCE OF EVF NCRNA REGULATION OF THE DLX GENES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 这个项目有两个主要目标。 首先，我们希望更好地了解RNA依赖的转录调控的新机制。 第二部分是对GABA能神经元分化和迁移的调控机制的研究。 第一个目标集中在如何新的非编码RNA，胚胎腹前脑（Evf），影响Dlx 5/6增强子的转录。 Evf ncRNA是第一个被发现的影响同源结构域蛋白转录活性的发育调控ncRNA。Evf ncRNA也是第一个显示与含同源框的转录因子合作和复合的ncRNA。因此，拟议的研究将是第一个调查体内作用的发育调节ncRNA依赖性调节增强子活性。RNA功能的机制研究的重要性从被认为涉及不同疾病的调节RNA的数量中显而易见。 这些包括：Prader Willi综合征、diGeorge综合征、Beckwith-Wiedeman综合征、脊髓小脑共济失调8型和Campomelic发育不良。 我们假设，Evfs是Dlx 1/2基因的效应子，调节神经元内Dlx 5和6的水平。 已知Dlx基因是GABA能适当迁移和/或存活到皮质和海马体所必需的。 最近，研究表明特定Dlx-1 GABA能亚群的丧失导致癫痫小鼠模型。 此外，Dlx 5印迹的改变与Rett综合征有关，影响GABA能中间神经元分化或迁移的特定方面。由于GABA能中间神经元功能的改变与癫痫、自闭症、精神分裂症和精神发育迟滞有关，因此对GABA能中间神经元正常发育的研究对于理解这些疾病的分子基础至关重要。 最终，我们希望更好地了解大脑中特定神经元亚群的正常发育将有助于预防和治疗人类神经系统疾病。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There are two main goals of this project. In the first, we hope to gain a better understanding of a novel mechansim of RNA depednent transcriptional regulation. In the second, we hope to gain a better understanding of how GABAergic neuronal differentiation and migration are comtrolled. The first goal focuses on how the novel non-coding RNAs, embryonic ventral forebrain (Evf), influence transcription of the Dlx 5/6 enhancer. Evf ncRNAs are the first developmentally regulated ncRNAs to be discovered that affect the transcriptional activity of a homeodomain protein. Evf ncRNAs are also the first ncRNAs shown to cooperate and complex with a homeobox-containing transcription factor. The proposed studies would therefore be the first to investigate the in vivo role of developmentally regulated ncRNA-dependent modulation of enhancer activity. The importance of mechanistic studies of RNA function is clear from the number of regulatory RNAs thought to be involved different diseases. These include: Prader Willi Syndrome, diGeorge Syndrome, Beckwith-Wiedeman syndrome, Spinocerebellar ataxia type 8, and campomelic dysplasia. We hypothesize that Evfs are effectors of the Dlx 1/2 genes, modulating the levels of Dlx 5 and 6 within neurons. Dlx genes are known to be required for proper GABAergic migration and/or survival to the cortex and hippocampus. Most recently, it was demonstrated that the loss of specific Dlx-1 GABAergic subpopulations results in a mouse model of epilepsy. In addition, alterations in Dlx 5 imprinting has been linked to Rett syndrome, affecting specific aspects of GABAergic interneuron differentiation or migration. Since altered GABAergic interneuron function has been linked to epilepsy, autism, schizophrenia, and mental retardation, studies on the normal development of GABAergic interneurons are critical to understanding the molecular bases for these diseases. Ultimately, we hope that a better understanding of the normal development of specific neuronal subpopulations in the brain will lead to the prevention and treatment of human neurological diseases.