Genetic Control of Basal Telencephalic Development

基础端脑发育的遗传控制

• 批准号: 8068645
• 负责人: JOHN L. R. RUBENSTEIN
• 金额: $ 38.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-20 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068645
• 关键词: Affective; Alleles; Autistic Disorder; Basal Ganglia; Basal Nucleus of Meynert; Brain region; Cell Nucleus; Cells; Chorea; Cognition; Cognitive; Corpus striatum structure; Defect; Development; Disease; Embryo; Embryonic Development; Emotions; Enhancers; Gene Expression; Genes; Genetic; Gilles de la Tourette syndrome; Globus Pallidus; Grant; Hippocampus (Brain); Huntington Disease; Interneurons; Label; Learning; Maps; Medial; Mediating; Mental Retardation; Mental disorders; Modeling; Molecular Analysis; Morphology; Motor; Movement; Movement Disorders; Neurons; Paper; Parkinson Disease; Phenotype; Property; Proteins; Publishing; Role; Schizophrenia; Specific qualifier value; Synapsins; Telencephalon; Testing; Tremor; Ventricular; addiction; cholinergic; classical conditioning; combinatorial; developmental genetics; mutant; neocortical; nervous system disorder; progenitor; public health relevance; research study; subventricular zone; tool; transcription factor

DESCRIPTION (provided by applicant): The cortex, striatum and pallidum are three key components of cortico-basal ganglia circuits - these circuits regulate limbic, associative and sensorimotor learning. The embryonic basal telencephalon generates subcortical nuclei and cortical interneurons that are required for the function of these circuits. As such, developmental defects of basal telencephalic development can have a profound influence on cognition, emotion and movement. Defects that alter sensorimotor learning can result in motor phenotypes, as exemplified by chorea, tremor and rigidity seen in disorders such as Huntington's disease and Parkinson's disease. Defects that alter limbic and associative learning can result in affective and cognitive defects that may underlie disorders such as Tourette's, Schizophrenia and addiction. The embryonic basal telencephalon primarily consists of the medial ganglionic eminence (MGE); it produces GABAergic and cholinergic projection neurons of the globus pallidus, nucleus basalis and adjacent regions, and GABAergic and cholinergic interneurons that disperse throughout the striatum and cortex. Thus, the basal telencephalon has a central role in generating components of cortical-basal ganglia circuits. An approach to elucidate the genetic underpinnings that regulate the basal telencephalon is to study the function of transcription factors that control the development and function of the neurons that are produced in this region. In this proposal, I describe experiments that study the functions of four transcription factors: Nkx2.1 (Aim 2), Lhx6 (Aim 3&4), Lhx7/8 (Aims 3&4) and Ldb1 (Aim 5). We hypothesize that combinatorial and unique functions of these four proteins participate in specifying the identity and properties of neurons generated by the embryonic basal telencephalon; the following schema provides the outline of our hypothesis. Aim 2 tests Nkx2.1 function in SVZ progenitors, pallidal projection neurons, and in the VZ of the most ventral regions of the basal telencephalon. Aim 3 studies how Lhx6 regulates MGE differentiation. Aim 4 tests whether Lhx6/Lhx7/8 coordinately regulate MGE development, and Aim 5 tests the function of Ldb1, and whether its phenotypes resemble Lhx6/7(8) mutants. In addition, we will perform fate mapping studies of cells produced in the embryonic basal telencephalon, using Cre-expressing alleles (Aim 1); these alleles will also be useful genetic tools for generating conditional mutants, such as in Aims 2 and 5. PUBLIC HEALTH RELEVANCE: The results from the proposed studies will provide basic information regarding the genetic and developmental mechanisms that control formation of brain regions that control cognition and movement. Disruption of these mechanisms can cause psychiatric and neurological disorders that include mental retardation, autism, schizophrenia, movement disorders and addiction.

描述（由申请人提供）：皮质、纹状体和苍白球是皮质基底神经节回路的三个关键组成部分——这些回路调节边缘、联想和感觉运动学习。胚胎基底端脑产生这些回路功能所需的皮质下核和皮质中间神经元。因此，基础端脑发育的发育缺陷会对认知、情感和运动产生深远的影响。改变感觉运动学习的缺陷可能会导致运动表型，例如亨廷顿病和帕金森病等疾病中出现的舞蹈症、震颤和僵硬。改变边缘系统和联想学习的缺陷可能会导致情感和认知缺陷，这些缺陷可能是抽动秽语症、精神分裂症和成瘾等疾病的根源。胚胎基底端脑主要由内侧神经节隆起（MGE）组成；它产生苍白球、基底核和邻近区域的 GABA 能和胆碱能投射神经元，以及分散在纹状体和皮质中的 GABA 能和胆碱能中间神经元。因此，基底端脑在生成皮质-基底神经节回路的组成部分中起着核心作用。阐明调节基底端脑的遗传基础的一种方法是研究控制该区域产生的神经元发育和功能的转录因子的功能。在本提案中，我描述了研究四种转录因子功能的实验：Nkx2.1（目标 2）、Lhx6（目标 3 和 4）、Lhx7/8（目标 3 和 4）和 Ldb1（目标 5）。我们假设这四种蛋白质的组合和独特功能参与指定胚胎基底端脑生成的神经元的身份和特性；下面的图表提供了我们假设的轮廓。目标 2 测试 SVZ 祖细胞、苍白球投射神经元以及基底端脑最腹侧区域的 VZ 中的 Nkx2.1 功能。目标 3 研究 Lhx6 如何调节 MGE 分化。目标 4 测试 Lhx6/Lhx7/8 是否协调调节 MGE 发育，目标 5 测试 Ldb1 的功能及其表型是否类似于 Lhx6/7(8) 突变体。此外，我们将使用表达 Cre 的等位基因对胚胎基底端脑中产生的细胞进行命运图谱研究（目标 1）；这些等位基因也将成为产生条件突变体的有用遗传工具，例如目标 2 和 5。 公共健康相关性：拟议研究的结果将提供有关控制认知和运动的大脑区域形成的遗传和发育机制的基本信息。这些机制的破坏可能导致精神和神经系统疾病，包括精神发育迟滞、自闭症、精神分裂症、运动障碍和成瘾。