Molecular Mechanisms of Cerebral Cortical Patterning

大脑皮层模式的分子机制

• 批准号: 7808067
• 负责人: ELIZABETH Elizabeth Grove
• 金额: $ 31.22万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808067
• 关键词: Adopted; Affect; Anterior; Area; Basal Ganglia; Binding; Brain; Cell Nucleus; Cells; Cerebral cortex; Cerebrum; Complex; Congenital Abnormality; Cortical Malformation; Data; Defect; Development; Disease; Dominant Negative Receptor; Dominant-Negative Mutation; Dorsal; Electroporation; Elements; FGF8 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Expression; Genes; Genetic; Goals; Growth Factor; Heparitin Sulfate; Human; Investigation; Ligands; Maps; Mediating; Mental disorders; Modeling; Molecular; Mus; Mutant Strains Mice; Neurologic; Pattern; Primordium; Research; Research Personnel; Role; Signal Transduction; Signaling Molecule; Source; Specific qualifier value; Structure; Syndrome; Telencephalon; Testing; Tissues; To specify; Up-Regulation; basal forebrain; base; cell type; discount; in utero; member; mutant; neocortical; postnatal; programs; receptor; receptor binding; research study; stem; transcription factor

DESCRIPTION (provided by applicant): My long term goal is to understand the mechanisms that initiate development of the mammalian cerebral cortex and control the formation of the cortical area map, the basic functional organization of the cortex. Findings should be relevant to understanding a wide variety of cortical birth defects, and diseases with later onset that stem from early cortical abnormalities. I propose here to continue a fruitful line of research in which my research group found that the secreted signaling molecule FGF8 regulates patterning of the cortical area map along the anterior/posterior (A/P) axis of the cortical primordium. This proposal has three aims. The first aim is to understand the A/P patterning signal better. At present we do not know if FGF8 and members of the same FGF subfamily form a signaling gradient to impart positional values to the cortex, or if they trigger a relay of other patterning mechanisms. Using mouse genetics we will generate mice with progressively lower levels of FGF8 subfamily ligands to determine if the cortical area map shows increasing shifts. If so, this would provide support for a gradient model, and discount the simplest relay model. To determine which FGF receptors relay the patterning signal, mice that lack combinations of FGF receptors will be analyzed to determine if their cortical maps show defects similar to an FGF8 deficiency. Because FGF/FGFR binding requires heparan sulfate (HS), we will evaluate the cortical area map in mice that lack HS in the cerebral cortex. Although other growth factors require HS, we want to know how loss of FGF signaling will affect area patterning. Will the map be homogenized, or will a default pattern be present? In Aim 2 we will use in utero electroporation of dominant negative FGFRs to determine if cortical cells detect levels of FGF signaling at a distance from the FGF8 source, and, when these levels change, respond by adopting a new area fate. We will also introduce a second source of FGF8 by electroporation and determine if multiple areas are duplicated, and if so, whether and how duplicate maps are ordered along a secondary A/P axis. In Aim 3, we will test the hypothesis that FGF signaling is also involved in the primary division of the telencephalon into the dorsal cerebral cortex and the nuclei of the basal forebrain. We will use mouse genetics, in utero electroporation, and attempted rescue of mouse mutants with excess FGFs to test whether FGF signaling suppresses the cortical fate and promotes ventral telencephalic fates.

描述（由申请人提供）：我的长期目标是了解启动哺乳动物大脑皮层发育的机制，并控制皮层区域图的形成，这是皮层的基本功能组织。研究结果应该有助于理解各种各样的皮质出生缺陷，以及源于早期皮质异常的后发疾病。在此，我建议继续我的研究小组发现，分泌的信号分子FGF8调节皮层原基前/后（a /P）轴上皮层区域图的模式。这项提议有三个目的。第一个目标是更好地理解A/P模式信号。目前，我们还不知道FGF8和相同FGF亚家族的成员是否形成了一个信号梯度，将位置值传递给皮层，或者它们是否触发了其他模式机制的中继。利用小鼠遗传学，我们将产生FGF8亚家族配体水平逐渐降低的小鼠，以确定皮质区域图是否显示增加的变化。如果是这样，这将为梯度模型提供支持，而忽略最简单的中继模型。为了确定哪种FGF受体传递模式信号，将对缺乏FGF受体组合的小鼠进行分析，以确定它们的皮质图谱是否显示出与FGF8缺乏相似的缺陷。由于FGF/FGFR结合需要硫酸肝素（HS），我们将评估大脑皮层中缺乏HS的小鼠的皮质区域图。虽然其他生长因子需要HS，但我们想知道FGF信号的丢失将如何影响区域模式。地图会被同质化吗，还是会出现默认模式？在Aim 2中，我们将在子宫内使用显性阴性fgfr的电穿孔来确定皮质细胞是否在远离FGF8源的距离处检测到FGF信号水平，并且当这些水平发生变化时，通过采用新的区域命运来做出反应。我们还将通过电穿孔引入FGF8的第二个来源，并确定是否有多个区域被复制，如果是这样，是否以及如何沿着次级a /P轴订购重复的地图。在Aim 3中，我们将验证FGF信号也参与了端脑向大脑背侧皮层和基底前脑核的初级分裂的假设。我们将使用小鼠遗传学，在子宫内电穿孔，并尝试拯救具有过量FGF的小鼠突变体，以测试FGF信号是否抑制皮层命运并促进腹侧端脑命运。