Regional and Genetic Diversity of Cortical Interneurons

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其形态、连接性和生理特性方面具有显著的多样性。近年来，许多研究人员专注于了解这种多样性是如何产生的。在该资助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其成熟特性（Butt等人，2005年）。特别是，我们发现，内侧和尾侧神经节隆起（MGE和CGE，分别），而在一起占绝大多数的皮质中间神经元，产生完全不重叠的队列。为了理解不同皮层中间神经元群体从这些结构产生的发育遗传机制，我们对含有同源框的基因Nkx 2 -1进行了功能的条件性丧失分析，该基因是目前唯一精确区分MGE和CGE的基因（Butt et al.，2008年）。这项研究表明，Nkx 2 -1作为一个分子切换开关，促进MGE衍生的皮质中间神经元群体的产生和抑制CGE衍生的中间神经元细胞的身份。在这项研究中，我们将探索Nkx 2 -1基因功能的正调控和负调控基因。首先，我们将进行Nkx 2 -1的结构功能分析，以检查其作为转录激活因子和抑制因子的能力。我们将通过探索Nkx 2 -1激活的基因的贡献来跟踪这一点，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CoupTF 1和CoupTF 2，CGE表达的基因与Nkx 2 -1互补表达，有助于生成来自该结构的中间神经元亚型。总之，这项研究将提供深入了解皮质中间神经元亚型产生的分子基础。越来越多的人认识到，皮质中间神经元通过维持CNS中的兴奋/抑制平衡，对神经系统的正常功能起着重要作用。此外，皮质中间神经元与包括癫痫、双相情感障碍和自闭症在内的神经系统疾病有关。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.