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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这个项目有两个主要目标。首先，我们希望对一种新的RNA转录调控机制有一个更好的了解。第二，我们希望更好地了解GABA能神经元的分化和迁移是如何被控制的。 第一个目标集中在新的非编码RNA，胚胎腹前脑(EVF)，如何影响DLX 5/6增强子的转录。EVF ncRNAs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节ncRNAs。EVF ncRNAs也是第一个与含有同源异型盒的转录因子相互作用和复合的ncRNAs。因此，这项拟议的研究将是第一次调查发育调节的ncRNA依赖的增强子活性调节在体内的作用。从被认为与不同疾病有关的调控RNA的数量来看，从机制上研究RNA功能的重要性是显而易见的。这些包括：Prader Willi综合征，DiGeorge综合征，Beckwith-Wiedeman综合征，脊髓小脑性共济失调8型，以及钟状核发育不良。 我们假设EVF是DLX1/2基因的效应者，调节神经元内DLX5和6的水平。已知DLX基因是GABA能向大脑皮层和海马区正常迁移和/或存活所必需的。最近，有人证明，特定的DLX-1 GABA能亚群的丢失导致了癫痫小鼠模型的建立。此外，DLX 5印迹的改变与Rett综合征有关，影响GABA能神经元间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、精神分裂症和智力低下有关，因此对GABA能中间神经元正常发育的研究对于了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导致人类神经疾病的预防和治疗。

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.