Genetic Control of Basal Telencephalic Development

端脑GABA能神经元在认知、运动和情绪中起着重要作用。失调症 这些神经元与癫痫、智力缺陷、自闭症和精神分裂症有关。在开发过程中， 内侧神经节隆起(MGE)前体细胞产生多种GABA能神经元，包括 生长抑素(SST+)和小白蛋白(PV+)皮质中间神经元(CINs)和基底节投射 神经元。MGE来源的神经元的身份由MGE前体细胞内的位置决定 指定它们的域，以及开发期间产生它们的时间。理解 支配空间和时间规范的转录网络对于决定基本的 端脑GABA能发育的机制，以及这些网络的功能障碍如何起作用 神经精神障碍。阐明MGE发生发展的转录网络 对于祖细胞及其衍生物，我们必须定义转录因子(TF)和调节元件(RES) 以及它们控制的编码区。 我们假设空间和时间上特定的转录回路控制端脑 GABA能神经元多样性。我们建议在小鼠身上进行一种基因和基因组相结合的实验，旨在 阐明调节MGE中产生的神经元发育的转录因子网络。我们的方法 利用遗传标记来选择性地纯化和操纵特定的MGE谱系，这将使我们能够 整合转录组和表观基因组数据。我们将在不同的MGE区域和在 使用活动具有地域性的新的时间可诱导的皱纹品系(目标1)。我们 然后将使用组蛋白芯片-Seq和ATAC-Seq来识别在空间上具有 和时间动态的表观基因组状态；我们还将使用TF CHIP-SEQ来确定体内结合位点 COUPTF1/2和MAF/MAFB(目标2)。从这些数据中，我们将开始揭示转录电路 控制MGE规格。电路模型将使用缺乏COUPTF1/2的小鼠突变体进行测试 我们假设的MAF/MAFB，TF在时间和空间上调节GABA能神经元多样性-- 依赖方式(目标3和4)。端脑GABA能发育过程中转录通路的研究 为理解包括RE在内的遗传途径提供了一个基本的框架， GABA能神经元的多样性，这可能在神经精神障碍中调节失调。

Telencephalic GABAergic neurons have central roles in cognition, movement and emotion. Dysfunction of these neurons is implicated in epilepsy, intellectual deficiency, autism and schizophrenia. During development, medial ganglionic eminence (MGE) progenitors generate a diversity of GABAergic neurons including Somatostatin (SST+) and Parvalbumin (PV+) cortical interneurons (CINs), and basal ganglia projection neurons. The identities of MGE-derived neurons are determined by the location within the MGE progenitor domain where they are specified, and the time during development when they are produced. Understanding the transcriptional networks that govern spatial and temporal specification is crucial for determining the basic mechanisms of telencephalic GABAergic development, and how dysfunction of these networks can contribute to neuropsychiatric disorders. To elucidate the transcriptional networks driving the development of MGE progenitors and their derivatives, we must define the transcription factors (TFs) and regulatory elements (REs) involved, as well as the coding regions that they control. We hypothesize that spatially and temporally specific transcriptional circuits control telencephalic GABAergic neuron diversity. We propose a combination of genetic and genomic experiments in mice aimed at elucidating the networks of TFs that regulate the development of neurons generated in the MGE. Our approach leverages genetic labeling to selectively purify and manipulate specific MGE lineages, which will allow us to integrate transcriptomic and epigenomic data. We will define RNA expression in different MGE regions and at different ages using novel temporally-inducible CreER lines whose activities are regionally specific (Aim 1). We will then use Histone ChIP-Seq and ATAC-Seq to identify genomic regions (candidate REs) that have spatially and temporally dynamic epigenomic states; we will also use TF ChIP-Seq to identify in vivo binding sites for COUPTF1/2 and MAF/MAFB (Aim 2). From these data, we will begin to uncover the transcriptional circuits controlling MGE specification. The circuit models will be tested using mouse mutants that lack COUPTF1/2 and MAF/MAFB, TFs that we hypothesize regulate GABAergic neuron diversity in a temporal- and spatial- dependent manner (Aim 3 & 4). Elucidating transcription circuits driving telencephalic GABAergic development provides a fundamental framework for understanding the genetic pathways, including the REs, that generate GABAergic neuron diversity and that may be dysregulated in neuropsychiatric disorders.