Regional and Genetic Diversity of Cortical Interneurons

描述（由申请人提供）：皮层中间神经元作为一个群体，在形态、连通性和生理特性方面被认为是非常多样化的。近年来，许多研究者都致力于了解这种多样性是如何产生的。在该基金的前一个资助周期中，我们能够证明不同皮层中间神经元群体的起源地点和时间预测了它们的成熟特性（Butt等，2005）。特别是，我们发现内侧和尾侧神经节突起（分别为MGE和CGE）虽然占皮质中间神经元的绝大多数，但却产生完全不重叠的队列。为了了解不同皮层中间神经元群体从这些结构中产生的发育遗传机制，我们对含有同源盒的基因Nkx2-1进行了条件功能丧失分析，该基因目前是唯一能够精确区分MGE和CGE的基因（Butt et al., 2008）。这项研究表明，Nkx2-1作为一个分子开关，促进mge来源的皮质中间神经元群体的产生，并抑制cge来源的中间神经元细胞身份。在本次资助中，我们将探索受Nkx2-1基因功能正调控和负调控的基因。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因子和抑制因子的能力。接下来，我们将探索Nkx2-1激活的基因的作用，并评估它们对具有特定亚型特征的皮质中间神经元产生的贡献。最后，我们将使用遗传学方法来探索cge衍生的中间神经元生成的多样性和时间，以及cge表达的与Nkx2-1互补表达的基因coutf1和coutf2如何促进从该结构衍生的中间神经元亚型的生成。总之，这项研究将提供对皮层中间神经元亚型产生的分子基础的见解。越来越多的人认识到，皮层中间神经元通过维持中枢神经系统的兴奋/抑制平衡，对神经系统的正常功能至关重要。此外，皮质中间神经元也与癫痫、双相情感障碍和自闭症等神经系统疾病有关。通过探索这些细胞类型产生的遗传机制，我们的建议有可能最终为靶向和操纵这一关键群体提供工具。

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.