The Regulation of MGE Proliferation and Cortical Interneuron Fate Determination

本程序研究了细胞增殖和皮质间神经元命运决定的相互作用，并探讨了改变中间神经元亚群的功能后果。生成正确数量和亚型的这些神经元对于正常运作的大脑的发育至关重要，项目2重点介绍了几个信号系统的相互作用，Notch，Wnt和Sonic Hedgehog(Shh)，这些系统对这一过程具有关键影响。 目的1.Notch信号调节许多器官的增殖和细胞命运，但Notch在内侧神经节隆起(MGE)生成中间神经元中的作用尚不清楚，MGE是关键的皮质间神经元亚群的来源。我们在微阵列筛选中发现了Notch配体Jagge-1，以寻找在背侧和腹侧MGE中差异表达的基因，从而提高了Notch信号调节神经元间命运决定的可能性。在目标1中，我们研究了背侧MGE中锯齿状-1功能的条件性损失。通过与项目1的相互作用，我们探索了我们在与这些突变体的初步研究中发现的周期蛋白D2表达的异常。通过与项目3的互动，我们将在器官类型切片培养中使用实时成像进一步探索与Notch相关的增殖行为变化。 目的2.在本项目的前四年中，我们已经证明了决定神经元命运的转录因子Nkx2.1在神经元发生过程中需要Shh信号的表达。我们还发现，表达Nkx2.1的MGE前体细胞的增殖需要“规范的”Wnt信号。在其他系统中，Shh信号可能是TCF4表达所必需的，TCF4是我们已经证明在皮质下端脑表达的“典型”Wnt信号的效应器。反过来，TCF4又被证明激活了非神经组织中Jagge1的表达。在目标2中，我们研究了Shh、Wnt和Notch信号效应器的潜在相互作用，因为它们与MGE的增殖和神经元间的命运有关。同样，与项目1和3的互动将是梳理出细胞周期和祖细胞分裂模式中潜在的缺陷的机制的关键，这些缺陷和模式是通过我们各种信号操纵产生的。 由于所有这三个信号系统的效应者，如皮质中间神经元本身，都与神经和神经精神疾病有关，项目2将产生几种新的选择性皮质中间神经元丢失的小鼠模型，其中一个有望产生可诱导的、可滴定的、有时间限制的中间神经元发生减少，供神经行为分析核心进行详细研究。这个项目的首要目标是将神经发生和神经亚型命运的关键机制与大脑功能的临床相关方面联系起来。

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.