Cortical Interneuron Fate Determination in the Medial Ganglionic Eminence

内侧神经节隆起的皮质中间神经元命运决定

• 批准号: 7192005
• 负责人: Stewart A Anderson
• 金额: $ 23.14万
• 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: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7192005
• 关键词: interneurons

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.

GABA能中间神经元在大脑皮层发育和功能中发挥着至关重要的作用，但人们对此知之甚少。 了解控制中间神经元命运决定的分子机制。大多数皮质 中间神经元起源于腹侧前脑的内侧神经节隆起（MGE），最近 证据已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检查分子信号如何 指定 MGE 内的中间神经元。为了实现这一目标，我们将结合使用体内和体外 功能获得和丧失的研究重点关注四种蛋白质： 1) Sonic Hedgehog (Shh)，一种促进腹侧神经管发育（包括 MGE）的形态发生素， 2) NKX2.1，Shh 信号传导的转录因子靶标，是正常 MGE 发育所需的， 3) LHX6，一种转录因子，位于MGE中Nkx2.1的下游，在中间神经元中表达 迁移到大脑皮层， 4) ARX1，也在迁移的中间神经元中表达，并且是正常中间神经元发育所必需的。 由于Shh、Nkx2.1和Arx1的突变与前脑发育异常有关 对于人类来说，这些研究为识别中间神经元规范的“分子密码”奠定了基础 这将增强我们对各种神经病理学疾病的理解和治疗方法。 此外，这些研究与 PPG 的其他目标高度协同，包括：分子控制 细胞周期蛋白 D2 和 Shh 对皮质和皮质下增殖的影响（项目 1 和 3），迁移细胞的作用 皮层下中间神经元在皮层增殖中的作用（项目 3）以及组织学、生理学和行为学 MGE 改变中间神经元输出的影响（项目 1 和 4）。总而言之，本次活动的总体目标 该项目旨在将胚胎前脑发育的临床相关改变与产后组织学联系起来 和功能表型。