The Regulation of MGE Proliferation and Cortical Interneuron Fate Determination

该项目研究了增殖和皮质中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发育正常功能的大脑至关重要，项目2关注几个信号系统的相互作用，Notch，Wnt和Sonic hedgehog（Shh），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信号调节许多器官中的增殖和细胞命运，但Notch在中间神经元生成中的作用是由内侧神经节隆起（MGE），关键的皮质中间神经元亚群的来源，是未知的。我们确定了Notch配体锯齿状蛋白-1基因差异表达的背侧与腹侧MGE的微阵列屏幕，提高了Notch信号调节interneuron命运决定的可能性。在目标1中，我们研究了背侧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表达异常。通过与项目3的互动，我们将使用器官型切片培养物中的实时成像进一步探索Notch相关的增殖行为改变。 目标2.在该项目的前四年中，我们已经证明了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期间需要Shh信号。我们还发现，Nkx2.1表达的MGE祖细胞的增殖需要“典型的”Wnt信号传导。在其他系统中，Shh信号可能是Tcf 4表达所必需的，Tcf 4是“经典”Wnt信号的效应子，我们已经证明它在皮质下端脑中表达。反过来，Tcf 4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信号效应子的潜在相互作用，因为它们与MGE增殖和中间神经元命运有关。同样，与项目1和3的相互作用对于梳理出通过我们的各种信号操纵产生的细胞周期和祖细胞分裂模式中的潜在缺陷机制至关重要。 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，与神经和神经精神疾病相关，项目2将产生几种新的选择性皮质中间神经元损失的小鼠模型，其中一种预计将产生诱导型，可滴定的，和有时限的减少中间神经元的发生，由神经行为分析核心进行详细调查。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脑功能的临床密切相关方面联系起来。

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.