Molecular Mechanisms of Cerebral Cortical Patterning

大脑皮层模式的分子机制

基本信息

批准号：
7928673
负责人：
ELIZABETH Elizabeth Grove
金额：
$ 1.15万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7928673
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

项目摘要

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开发的机制，并控制皮质区域图的形成，这是皮层的基本功能组织。发现应该与了解各种皮质先天缺陷以及以后发作的疾病有关，该疾病源于早期皮质异常。我在这里提议继续进行一项富有成果的研究线，在该研究中，我的研究小组发现，分泌的信号分子FGF8调节沿着皮质原始的前/后轴（A/P）轴的皮质区域图的模式。该提议有三个目标。第一个目的是更好地了解A/P图案信号。目前，我们不知道FGF8和同一FGF亚家族的成员是否形成信号传导梯度，以将位置值赋予皮层，或者它们是否触发其他模式机制的继电器。使用小鼠遗传学，我们将生成具有逐渐较低水平的FGF8亚家族配体的小鼠，以确定皮质面积图是否显示出增加的变化。如果是这样，这将为梯度模型提供支持，并打折最简单的继电器模型。为了确定哪些FGF受体传递模式信号，将分析缺乏FGF受体组合的小鼠，以确定其皮质图是否显示出类似于FGF8缺乏症的缺陷。由于FGF/FGFR结合需要硫酸乙酰肝素（HS），因此我们将评估缺乏大脑皮质中HS的小鼠的皮质面积图。尽管其他生长因素需要HS，但我们想知道FGF信号的损失将如何影响区域模式。该地图会均匀化，还是存在默认模式？在AIM 2中，我们将用于主要负FGFR的子宫电穿孔，以确定皮质细胞是否检测到距FGF8源距离处的FGF信号传导水平，当这些水平发生变化时，通过采用新面积的命运来做出响应。我们还将通过电穿孔引入第二个FGF8来源，并确定是否重复多个区域，如果是，是否以及如何沿二次A/P轴订购了重复的映射。在AIM 3中，我们将检验以下假设：FGF信号传导也参与尾脑的一级分裂到背脑皮层和基底前脑的核中。我们将在子宫电穿孔中使用小鼠遗传学，并尝试营救过多的FGF的小鼠突变体来测试FGF信号传导是否抑制皮质命运并促进腹侧脑透露率命运。