Regional and Genetic Diversity of Cortical Interneurons

皮质中间神经元的区域和遗传多样性

• 批准号: 8721099
• 负责人: GORDON J FISHELL
• 金额: $ 47.28万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-23 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721099
• 关键词: Accounting; Autistic Disorder; Biochemical; Bipolar Disorder; Cell physiology; Cells; Epilepsy; Equilibrium; Funding; Generations; Genes; Genetic; Genetic Variation; Grant; Homeobox; Human; Inborn Genetic Diseases; Interneurons; Investigation; Lead; Link; Logic; Maintenance; Maps; Medial; Methods; Molecular; Morphology; Nervous System Physiology; Patients; Phenotype; Physiological; Population; Production; Property; Research Personnel; Signal Transduction; Structure; Time; Transcription Coactivator; Transcription Repressor/Corepressor; base; cell type; cohort; developmental genetics; drug discovery; gain of function; gene function; genetic profiling; homeodomain; insight; loss of function; nervous system disorder; progenitor; programs; tool

DESCRIPTION (provided by applicant): Cortical interneurons as a population are recognized to be remarkably diverse in terms of their morphology, connectivity and physiological properties. In recent years numerous investigators have focused on understanding how this diversity is generated. In the previous funding cycle of this grant we were able to demonstrate that the place and time of origin of different cortical interneuron populations predicts their mature properties (Butt et al., 2005). In particular we found that the medial and caudal ganglionic eminences (MGE and CGE, respectively), while together accounting for the vast majority of cortical interneurons, produce entirely non-overlapping cohorts. In an effort to understand the developmental genetic mechanisms by which different cortical interneuron populations arise from these structures, we undertook a conditional loss of function analysis of the homeobox-containing gene Nkx2-1, which at present is the only gene that precisely distinguishes between the MGE and CGE (Butt et al., 2008). This study revealed that Nkx2-1 acts as a molecular toggle switch that promotes the generation of MGE-derived cortical interneuron populations and represses the CGE-derived interneuron cell identities. In this grant we will explore the genes that are both positively and negatively regulated by Nkx2-1 gene function. First we will undertake a structure function analysis of Nkx2-1 to examine its ability to act as a transcriptional activator and repressor. We will follow this by exploring the contribution of genes that are activated by Nkx2-1 and evaluate their contributions to the production of cortical interneurons with specific subtype character. Finally we will use a genetic approach to explore the diversity and timing of CGE-derived interneuron generation and how CoupTF1 and CoupTF2, CGE-expressed genes with complementary expression to Nkx2-1, contribute to the generation of the interneuron subtypes derived from this structure. Together, this study will provide insights into the molecular basis by which cortical interneuron subtypes are generated. Increasingly it is being recognized that cortical interneurons through their maintenance of the excitatory/inhibitory balance in the CNS are central to the normal function of the nervous system. In addition, cortical interneurons have been implicated in neurological disorders including epilepsy, bipolar disorders and autism. Our proposal by exploring the genetic mechanisms by which these cell types are generated has the potential to ultimately provide tools for targeting and manipulating this critical population.

描述（由申请人提供）：在其形态，连通性和生理特性方面，认为作为人群的皮质中间神经元被认为是非常多样化的。近年来，许多研究人员都专注于了解这种多样性的产生。在这笔赠款的先前资金周期中，我们能够证明不同皮质间神经元种群的起源地点和时间预测了它们的成熟特性（Butt等，2005）。特别是，我们发现内侧和尾神经节的隆起（分别为MGE和CGE），同时占绝大多数皮质中间神经元的同时，会产生完全非重叠的同类群体。为了了解不同皮质间神经元种群由这些结构产生的发育遗传机制，我们对含同基因的基因NKX2-1进行了有条件的功能分析，目前是唯一可以与MGE和CGE之间的唯一基因（Butt等，2008）。这项研究表明，NKX2-1充当分子拨动开关，可促进MGE衍生的皮质间神经元种群的产生并抑制CGE衍生的中间神经元细胞的身份。在这笔赠款中，我们将探索由NKX2-1基因功能对既积极和负面调节的基因。首先，我们将进行NKX2-1的结构函数分析，以检查其充当转录激活因子和阻遏物的能力。我们将通过探索NKX2-1激活的基因的贡献，并评估它们对具有特定亚型特征的皮质中间神经元的贡献。最后，我们将使用一种遗传方法来探索CGE衍生的中间神经元产生的多样性和时机，以及如何使用与NKX2-1互补的CGEPTF2，CGE表达的基因互补的基因，有助于产生从这种结构中得出的中间子类型。总之，这项研究将提供有关生成皮质间神经元亚型的分子基础的见解。越来越多地认识到，通过维持中枢神经系统的兴奋性/抑制平衡，皮质中间神经元对神经系统的正常功能至关重要。此外，皮质中间神经元与神经系统疾病有关，包括癫痫，双相情感障碍和自闭症。通过探索这些细胞类型的遗传机制，我们的建议有可能最终提供针对和操纵这一关键人群的工具。