The Regulation of MGE Proliferation and Cortical Interneuron Fate Determination

MGE增殖的调控和皮质中间神经元的命运决定

• 批准号: 8698470
• 负责人: Stewart A Anderson
• 金额: $ 66.14万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8698470
• 关键词: Ablation; Address; Anxiety Disorders; Area; Attention; Autistic Disorder; Behavior; Behavioral; Brain; Brain imaging; Cell Cycle; Cell Proliferation; Cells; Clinical; Defect; Development; Disease; Dorsal; Epilepsy; Erinaceidae; Excision; Funding; Gene Targeting; Generations; Genes; Genetic; Goals; Human; Image; Interneurons; Intractable Epilepsy; Investigation; Life; Ligands; Link; Medial; Mediating; Molecular Abnormality; Mutation; Neurodevelopmental Disorder; Neurologic; Neurons; Organ; Output; Pathology; Pattern; Process; Prosencephalon; Publishing; Regulation; Role; Schizophrenia; Signal Transduction; Slice; Source; System; Telencephalon; Time; Tissues; Transgenic Mice; Transplantation; Variant; base; cellular imaging; cyclin D2; embryonic stem cell; gain of function; improved; in vivo; jagged1 protein; loss of function; mouse model; mutant; neurobehavioral; neurogenesis; neuropsychiatry; notch protein; novel; overexpression; progenitor; programs; relating to nervous system; smoothened signaling pathway; success; transcription factor

This Program examines the interaction of proliferation and cortical interneuron fate determination and probes the functional consequences of altering interneuron subpopulations. Generating the correct number and subtypes of these neurons is crucial for the development of a normally functioning brain, and Project 2 focuses on the interacting roles of several signaling systems, Notch, Wnt, and Sonic hedgehog (Shh), that critically influence this process. Aim 1. Notch signaling regulates proliferation and cell fate in many organs, but a role for Notch in interneuron generation by the medial ganglionic eminence (MGE), the source of critical cortical interneuron subpopulations, is not known. We identified the Notch ligand Jagged-1 in a microarray screen for genes differentially expressed in the dorsal versus the ventral MGE, raising the possibility that Notch signaling regulates interneuron fate determination. In Aim 1, we examine conditional loss of Jagged-1 function in the dorsal MGE. Via interactions with Project 1, we explore abnormalities of cyclin D2 expression that we have identified in preliminary studies with these mutants. Via interactions with Project 3, we will further explore Notch-related alterations in proliferative behavior using live imaging in organotypic slice cultures. Aim 2. During the first four years of this Program we have shown that the expression of the interneuron fate-determining transcription factor, Nkx2.1, requires Shh signaling during interneuron genesis. We also found that proliferation of Nkx2.1-expressing, MGE progenitors requires "canonical" Wnt signaling. In the other systems, Shh signaling can be necessary for the expression of Tcf4, an effector of "canonical" Wnt signaling, that we have shown to be expressed in the subcortical telencephalon. Tcf4, in turn, has been shown to activate the expression of Jagged 1 in non-neural tissue. In Aim 2 we examine potential interactions of Shh, Wnt, and Notch signaling effectors as they relate to MGE proliferation and interneuron fate. Again, interaction with Projects 1 & 3 will be critical for teasing out the mechanisms underlying defects in cell cycle and modes of progenitor division that are generated through our various signaling manipulations. As effectors of all three of these signaling systems, like cortical interneurons themselves, are associated with neurological and neuropsychiatric disease, Project 2 will generate several novel mouse models of selective cortical interneuron losses, one of which is expected to produce an inducible, titratable, and time-limited reduction of interneuron genesis, for detailed investigation by the Neurobehavioral Analysis Core. The overarching goal of this project is to link critical mechanisms in neurogenesis and neural subtype fate with clinically germane aspects of brain function.

该计划检查增殖和皮质中间神经元命运决定的相互作用，并探讨改变中间神经元亚群的功能后果。生成这些神经元的正确数量和亚型对于正常功能的大脑的发育至关重要，项目 2 重点关注几个信号系统（Notch、Wnt 和 Sonic hedgehog (Shh)）之间的相互作用，这些信号系统对这一过程产生了至关重要的影响。 目标 1. Notch 信号传导调节许多器官中的增殖和细胞命运，但 Notch 在内侧神经节隆起 (MGE)（关键皮质中间神经元亚群的来源）生成中间神经元中的作用尚不清楚。我们通过微阵列筛选在背侧和腹侧 MGE 中差异表达的基因，鉴定出了 Notch 配体 Jagged-1，这提高了 Notch 信号传导调节中间神经元命运决定的可能性。在目标 1 中，我们检查了背侧 MGE 中 Jagged-1 功能的条件性丧失。通过与项目 1 的相互作用，我们探索了在这些突变体的初步研究中发现的细胞周期蛋白 D2 表达异常。通过与项目 3 的互动，我们将使用器官切片培养物中的实时成像进一步探索与 Notch 相关的增殖行为改变。 目标 2. 在该计划的前四年中，我们发现中间神经元命运决定转录因子 Nkx2.1 的表达在中间神经元发生过程中需要 Shh 信号传导。我们还发现表达 Nkx2.1 的 MGE 祖细胞的增殖需要“规范的”Wnt 信号传导。在其他系统中，Shh 信号传导可能是 Tcf4 表达所必需的，Tcf4 是“典型”Wnt 信号传导的效应子，我们已证明 Tcf4 在皮质下端脑中表达。反过来，Tcf4 已被证明可以激活非神经组织中 Jagged 1 的表达。在目标 2 中，我们研究了 Shh、Wnt 和 Notch 信号传导效应器的潜在相互作用，因为它们与 MGE 增殖和中间神经元命运相关。同样，与项目 1 和 3 的相互作用对于梳理细胞周期缺陷的潜在机制和通过我们的各种信号操作产生的祖细胞分裂模式至关重要。 由于所有这三个信号系统的效应器（如皮质中间神经元本身）都与神经系统和神经精神疾病相关，因此项目 2 将生成几种新型选择性皮质中间神经元丢失的小鼠模型，其中一个预计将产生一种可诱导的、可滴定的和限时减少中间神经元发生，供神经行为分析核心进行详细研究。该项目的总体目标是将神经发生和神经亚型命运的关键机制与脑功能的临床相关方面联系起来。