Genetic Analysis of Cortical Development in Mice

小鼠皮质发育的遗传分析

• 批准号: 6573722
• 负责人: Susan K McConnell
• 金额: $ 39.86万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6573722
• 关键词: biological signal transduction; bone morphogenetic proteins; cell differentiation; cell proliferation; cerebral cortex; choroid plexus; fibroblast growth factor; genetically modified animals; glia; growth factor receptors; hippocampus; in situ hybridization; laboratory mouse; neocortex; neurogenesis; neurogenetics; telencephalon; terminal nick end labeling

DESCRIPTION (provided by applicant): An early step in the creation of the nervous system is the generation of neurons and glial cells, the building blocks of all neural circuits. During development, some cells exit the cell cycle and differentiate into neurons or glia, while others reenter the cell cycle and remain as progenitors. Both extrinsic factors (such as peptide growth factors) and intrinsic factors (such as cell-surface receptors) play important roles in the regulation of proliferation, fate specification, and differentiation. The goal of the present proposal is to test the roles of these molecules in neurogenesis and patterning of the developing cerebral cortex. Such studies have been hampered by the realization that relatively small numbers of gene families are utilized over and over during development, with the outcome of a signaling event determined largely by the type of the responding cell and the developmental context in which a signal is presented. Because of the repeated utilization of a small set of signals at a number of different times, places, and stages of development, it can be difficult to use genetics explore the role of a particular signaling system in a particular tissue in vivo. We will use conditional molecular genetic techniques in the mouse to explore the role of extrinsic signaling molecules and their receptors in the production of cortical neurons in vivo, and to compare directly the roles of these signaling systems at distinct times during development. By using mice that express the bacteriophage recombinase Cre in telencephalic progenitor cells, we will generate conditional knockouts or express dominant negative forms of signaling molecules in the developing brain. We will focus on the roles of Bone Morphogenetic Proteins (BMPs) and Fibroblast Growth Factors (FGFs), in the control of patterning, cell number, phenotype, and differentiation in the developing cerebral cortex, Our first aim addresses the hypothesis that BMP signaling induces the development of the dorsal midline. We will perform conditional knockouts of Bmp4 or its major receptor Bmpr1a, either alone or in combination with a null mutation in Bmpr1b, at the earliest stages of telencephalic specification and analyze the effects of each mutation on cerebral patterning and dorsal midline development. The second aim is to examine the role of FGF signaling in the development of anterior-posterior patterning and the formation of cortical areas. We will generate conditional knockouts of the FGF receptors Fgfr1 and Fgfr2, alone or in combination with a null mutation in Fgfr3, to assess the roles of these signaling molecules in patterning cortical areas, Our third aim uses genetics to explore the opposing roles of BMP and FGF signaling in cortical cell proliferation (stimulated by FGFs), neurogenesis (promoted by BMPS), and the production of glia.

描述（由申请人提供）：神经系统创建的早期步骤是神经元和神经胶质细胞的生成，它们是所有神经回路的构建块。在发育过程中，一些细胞退出细胞周期并分化为神经元或神经胶质，而另一些细胞重新进入细胞周期并保持为祖细胞。外在因子（如肽生长因子）和内在因子（如细胞表面受体）在增殖、命运特化和分化的调节中起重要作用。本研究的目的是测试这些分子在发育中的大脑皮层的神经发生和模式中的作用。这样的研究受到了阻碍，因为人们认识到，在发育过程中，相对较少的基因家族被反复利用，信号事件的结果主要取决于响应细胞的类型和信号呈现的发育背景。由于在许多不同的时间、地点和发育阶段重复使用一小组信号，因此很难使用遗传学来探索特定信号系统在体内特定组织中的作用。我们将在小鼠中使用条件分子遗传学技术来探索外源性信号分子及其受体在体内皮质神经元产生中的作用，并直接比较这些信号系统在发育过程中不同时间的作用。通过使用在端脑祖细胞中表达噬菌体重组酶Cre的小鼠，我们将在发育中的大脑中产生条件性敲除或表达显性阴性形式的信号分子。我们将集中在骨形态发生蛋白（BMP）和成纤维细胞生长因子（FGF）的作用，在控制图案，细胞数量，表型，并在发育中的大脑皮层分化，我们的第一个目标解决的假设，BMP信号诱导背中线的发展。我们将在端脑特化的最早阶段单独或与Bmpr1b中的无效突变组合进行Bmp4或其主要受体Bmpr1a的条件性敲除，并分析每个突变对大脑模式和背中线发育的影响。第二个目的是研究FGF信号在前后图案形成和皮质区形成中的作用。我们将产生FGF受体Fgfr 1和Fgfr 2的条件性敲除，单独或与Fgfr 3中的无效突变相结合，以评估这些信号分子在图案化皮质区中的作用。我们的第三个目标是使用遗传学来探索BMP和FGF信号在皮质细胞增殖（由FGF刺激）、神经发生（由BMPS促进）和神经胶质细胞产生中的相反作用。