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.

该程序研究了增殖和皮质间神经元命运确定的相互作用，并探测了改变中间神经元亚群的功能后果。产生这些神经元的正确数量和亚型对于开发正常运行的大脑至关重要，项目2重点介绍了多种信号系统，Notch，Wnt和Sonic Hedgehog（SHH）的相互作用作用，这会对这一过程产生严重影响。 AIM1。Notch信号传导调节许多器官中的增殖和细胞命运，但尚不清楚由内侧神经节隆起（MGE）（MGE）（MGE）在note元中产生的作用。我们在微阵列屏幕中鉴定了缺口锯齿状1，用于在背侧和腹侧MGE中差异表达的基因，从而提高了Notch信号传导调节中间神经元命运的可能性。在AIM 1中，我们检查了背MGE中锯齿状1功能的有条件丧失。通过与项目1的相互作用，我们探讨了我们在这些突变体的初步研究中发现的细胞周期蛋白D2表达的异常。通过与项目3的相互作用，我们将在器官切片培养物中使用实时成像进一步探索与Notch相关的增殖行为变化。 AIM 2。在该程序的前四年中，我们表明，中间命运的转录因子NKX2.1的表达需要在间神经元创世纪期间进行SHH信号传导。我们还发现，表达NKX2.1的增殖，MGE祖细胞需要“规范”的Wnt信号传导。在其他系统中，SHH信号对于TCF4的表达是必需的，TCF4是“规范” Wnt信号的效应子，我们已证明在皮层端脑下表达。反过来，TCF4已被证明会激活非神经组织中锯齿状1的表达。在AIM 2中，我们检查了SHH，Wnt和Notch信号传导效应子与MGE增殖和中间命运有关的潜在相互作用。同样，与项目1和3的相互作用对于通过我们的各种信号操作产生的细胞周期和祖细胞划分模式中的缺陷和模式中的机制至关重要。 作为所有这三个信号系统的效应子，例如皮质间神经元本身，都与神经和神经精神病有关，项目2将产生几种选择性皮质间神经元损失的新型鼠标模型，其中一种预计会产生可诱导的，可滴定的，可滴定和时间限制的核元分析，以详细研究Neurobebece，以进行详细的核心研究。该项目的总体目标是将神经发生和神经亚型命运中的关键机制与脑功能的临床延伸方面联系起来。