Genetic Control of Basal Telencephalic Development

描述(申请人提供)：皮质、纹状体和苍白球是皮质-基底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间神经元。因此，基础端脑发育的发育缺陷可能会对认知、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、震颤和僵硬。改变边缘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症、精神分裂症和成瘾等障碍的基础。胚胎基底端脑主要由内侧神经节隆起(MGE)组成，在苍白球、基底核及邻近区域产生GABA能和胆碱能投射神经元，GABA能和胆碱能中间神经元分布于纹状体和皮质。因此，基底端脑在皮质-基底节环路的成分产生中起中心作用。要阐明调节基础端脑的遗传基础，一种方法是研究转录因子的功能，这些转录因子控制着该区域产生的神经元的发育和功能。在这个提案中，我描述了研究四个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的功能参与指定由胚胎基础端脑产生的神经元的身份和特性；以下模式提供了我们的假设的大纲。目的研究Nkx2.1在SVZ前体细胞、苍白球投射神经元和基底端脑最腹侧VZ的功能。目的3研究Lhx6对MGE分化的调控作用。目的4检测Lhx6/Lhx7/8是否协同调节MGE的发育，目的5检测Ldb1的功能，以及其表型是否与Lhx6/7(8)突变体相似。此外，我们将使用表达Cre的等位基因(Aim 1)对胚胎基底端脑中产生的细胞进行命运图谱研究；这些等位基因也将是产生条件突变的有用遗传工具，如在AIMS 2和5中。 与公共健康相关：拟议研究的结果将提供有关控制大脑区域形成的遗传和发育机制的基本信息，这些区域控制认知和运动。这些机制的破坏可能导致精神和神经障碍，包括智力低下、自闭症、精神分裂症、运动障碍和成瘾。

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.