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）：皮质中间神经元作为一个群体被认为在形态、连接性和生理特性方面具有显着的多样性。近年来，许多研究人员致力于了解这种多样性是如何产生的。在本次资助的上一个资助周期中，我们能够证明不同皮质中间神经元群体的起源地点和时间可以预测它们的成熟特性（Butt et al., 2005）。特别是，我们发现内侧和尾部神经节隆起（分别为 MGE 和 CGE）虽然共同占据了皮质中间神经元的绝大多数，但产生了完全不重叠的群体。为了了解不同皮质中间神经元群体由这些结构产生的发育遗传机制，我们对含有同源盒的基因 Nkx2-1 进行了条件性功能丧失分析，该基因是目前唯一能够精确区分皮质中间神经元群体的基因。 MGE 和 CGE（Butt 等人，2008）。这项研究表明，Nkx2-1 作为分子切换开关，促进 MGE 衍生的皮质中间神经元群体的生成并抑制 CGE 衍生的中间神经元细胞身份。在这笔资助中，我们将探索受 Nkx2-1 基因功能正向和负向调节的基因。首先，我们将对 Nkx2-1 进行结构功能分析，以检查其作为转录激活子和阻遏子的能力。接下来，我们将探索 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产生的贡献。最后，我们将使用遗传方法来探索 CGE 衍生的中间神经元生成的多样性和时间安排，以及 CoupTF1 和 CoupTF2（与 Nkx2-1 表达互补的 CGE 表达基因）如何有助于衍生自该结构的中间神经元亚型的生成。总之，这项研究将深入了解皮质中间神经元亚型产生的分子基础。人们越来越认识到，皮质中间神经元通过维持中枢神经系统的兴奋/抑制平衡，对于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。我们通过探索这些细胞类型产生的遗传机制的建议有可能最终提供用于靶向和操纵这一关键群体的工具。