Cortical Interneuron Fate Determination in the Medial Ganglionic Eminence

GABA能中间神经元在大脑皮层发育和功能中起关键作用，但几乎不起作用 了解控制神经元间命运决定的分子机制。皮质层最多 中间神经元起源于腹侧前脑的内侧神经节隆起(MGE)，在那里 已有证据开始进一步确定皮质中间神经元不同亚群的起源 (徐...安德森，2004)。下面描述的实验旨在研究分子信号如何 指定MGE内的中间神经元。为了实现这一目标，我们将使用体内和体外相结合的方法 功能的得失研究主要集中在四种蛋白质上： 1)Sonic Hedgehog(Shh)，一种促进腹侧神经管发育的形态因子，包括MGE， 2)Nkx2.1，Shh信号的转录因子靶点，正常的MGE发育所需的， 3)转录因子LHX6，位于MGE中Nkx2.1下游，在中间神经元中表达 迁移到大脑皮层， 4)ARX1在迁移的中间神经元中也有表达，是正常的中间神经元发育所必需的。 自从Shh、Nkx2.1和Arx1基因突变与发育性前脑异常有关以来， 人类，这些研究为确定神经元间质规范的“分子密码”奠定了基础 这将增强我们对各种神经病理情况的理解和治疗方法。 此外，这些研究与PPG的其他目标高度协同，包括分子控制 Cyclin D2和Shh对皮质和皮质下增殖的影响(项目1和3)，迁移的作用 皮质下中间神经元与皮质增殖(项目3)及其组织学、生理学和行为学研究 MGE改变中间神经元输出的影响(项目1和4)。总而言之，这一行动的首要目标是 该项目是将胚胎前脑发育的临床相关变化与出生后组织学联系起来 和功能表型。

GABAergic interneurons perform crucial roles in cerebral cortical development and function, but little is known about the molecular mechanisms that control interneuron fate determination. Most cortical interneurons originate in the medial ganglionic eminence (MGE) of the ventral forebrain, where recent evidence has begun to further define the origins of distinct subgroups of cortical interneurons (Xu...Anderson, 2004). The experiments described below are designed to examine how molecular signals specify interneurons within the MGE. To achieve this goal we will use a combination of in vivo and in vitro gain and loss of function studies focused on four proteins: 1) Sonic Hedgehog (Shh), a morphogen that promotes ventral neural tube development including the MGE, 2) NKX2.1, a transcription factor target of Shh signaling that is required for normal MGE development, 3) LHX6, a transcription factor that is, downstream of Nkx2.1 in the MGE and is expressed in interneurons migrating to the cerebral cortex, 4) ARX1, also expressed in migrating interneurons, and required for normal interneuron development. Since mutations inShh, Nkx2.1 and Arx1 have been linked to developmental forebrain abnormalities in humans, these studies lay the groundwork for identifying the "molecular code" for interneuron specification that will enhance our understanding of and treatment approaches for a variety of neuropathologic conditions. In addition, these studies are highly synergistic with other aims of the PPG including; the molecular control of cortical and subcortical proliferation by cyclin D2 and Shh (Projects 1 and 3), the role of migratory subcortical interneurons in cortical proliferation (Project 3) and the histological, physiological and behavioral effects of altered interneuron output by the MGE (Projects 1 and 4). In sum, the overarching goal of this project is to link clinically relevant alterations in embryonic forebrain development with postnatal histological and functional phenotypes.