Molecular Mechanisms of Cerebral Cortical Patterning

大脑皮层模式的分子机制

• 批准号: 8890239
• 负责人: ELIZABETH Elizabeth Grove
• 金额: $ 35.55万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890239
• 关键词: Address; Area; Autistic Disorder; BHLH Protein; Binding; Biochemical; Biological Models; Candidate Disease Gene; Cells; Cerebral cortex; Cerebrum; Characteristics; Complex; Data Analyses; Defect; Development; Disease; Electroporation; Embryo; Enhancers; Event; FGF8 gene; FGFRL1 gene; FLRT3 gene; Family; Feedback; Fibroblast Growth Factor; Fibroblast Growth Factor 8; Fibroblast Growth Factor Receptors; Fibronectins; Gene Expression; Gene Expression Profile; Gene Transfer; Generations; Genes; Genetic; Glycoproteins; Goals; Growth; Health; Human; Impaired cognition; In Vitro; Integral Membrane Protein; Leucine; Life; Light; Link; Maps; Mediation; Methods; Molecular; Motivation; Mus; PI3K/AKT; Pathway interactions; Pattern; Population; Prefrontal Cortex; Primordium; Proteins; Research; Retinal; Role; Schedule; Schizophrenia; Sensory; Signal Transduction; Signaling Molecule; Site; Source; Specific qualifier value; Spinal Cord; Structure; Syndrome; Testing; Time; Tissues; Transcription Repressor/Corepressor; Ursidae Family; Work; base; cellular transduction; deep sequencing; developmental disease; differential expression; fatty acid-binding proteins; gene function; in utero; in vivo; inhibitor/antagonist; member; mitral cell; morphogens; mutant; neocortical; olfactory bulb; protein complex; protein expression; receptor; research study; sensory stimulus; stem; transcription factor; transcriptome sequencing

DESCRIPTION (provided by applicant): Longterm goals of the proposed research are to understand the mechanisms that initiate development of mammalian cerebral cortex, and control formation of the neocortical area map. Findings should be relevant to a range of human disorders that stem from developmental defects in cerebral cortex. This proposal, which has three aims, is based on evidence that the signaling molecule Fibroblast Growth Factor (FGF) 8 acts as a graded morphogen in the embryonic mouse neocortical primordium (NP), and initiates a genetic cascade that leads to formation of the area map. Strikingly, ectopic FGF8 in the NP can induce duplicate areas, and even complex maps. Aim 1 is built on a previous, systematic search for candidate genes downstream of FGF8 and next in the cascade that leads to cortical regionalization. We used deep sequencing (RNA-Seq) to compare transcriptomes of NP tissue, exposed to different concentrations of FGF8 on different time schedules, mimicking the natural gradient of FGF8, and the natural timed exposure of NP to FGF8. We have identified several candidate genes downstream of FGF8 with regional expression in the NP and a link with embryonic patterning elsewhere. We will use mouse genetics and in utero microelectroporation for gene transfer into living mouse embryos to determine the role of the candiate genes in patterning the area map. Aim 2 will investigate how FGF8 interacts with FGF receptors (FGFRs), and how potential endogenous FGFR inhibitors and enhancers control the FGF8 grandient, and, consequently, development of the area map. Aim 3 will investigate the olfactory bulb primordium (OBP) as a promising model system for determining how bounded areas are established in embryonic cortex. The OBP is a distinct bounded domain long before any neocortical areas. We have evidence that FGF8 can induce a secondary OBP and will investigate FGF8 induction of the OBP further in this aim. The OBP is derived from tissue immediately adjacent to the areas of prefrontal cortex. Experiments will explore how these different cortical structures are separated from one another in development. Partial motivation for our experiments here are claims of a common link between olfactory deficits and schizophrenia and autism.

描述(申请人提供)：拟议研究的长期目标是了解启动哺乳动物大脑皮层发育的机制，并控制新皮质区域图的形成。这些发现应该与一系列人类疾病相关，这些疾病源于大脑皮层发育缺陷。这一建议有三个目的，基于信号分子成纤维细胞生长因子8在胚胎小鼠新皮质原基(NP)中起分级形态作用的证据，并启动了导致区域图形成的遗传级联。值得注意的是，NP中的异位FGF8可以诱导重复的区域，甚至是复杂的地图。AIM 1建立在之前对FGF8下游的候选基因和导致皮质区域化的级联中的下一个候选基因的系统搜索的基础上。我们使用深度测序(RNA-Seq)来比较不同浓度的FGF8在不同的时间段暴露于NP组织的转录本，模拟FGF8的自然梯度，以及NP对FGF8的自然定时暴露。我们已经确定了FGF8下游的几个候选基因，这些基因在NP中有区域表达，并与其他地方的胚胎模式有关。我们将利用小鼠遗传学和子宫内微电穿孔技术将基因转移到活的小鼠胚胎中，以确定候选基因在绘制区域图中的作用。目的2研究FGF8如何与成纤维细胞生长因子受体(FGFRs)相互作用，以及潜在的内源性FGFR抑制剂和增强剂如何控制FGF8的作用，从而形成区域图。目的3将研究嗅球原基(OBP)作为一个很有前途的模型系统来确定胚胎皮质中如何建立有界区域。早在任何新皮质区域之前，OBP就是一个明显的有界区域。我们有证据表明，FGF8可以诱导继发性OBP，并将进一步研究FGF8对OBP的诱导。OBP来源于紧邻前额叶皮质区域的组织。实验将探索这些不同的皮质结构在发育过程中是如何相互分离的。我们实验的部分动机是声称嗅觉缺陷与精神分裂症和自闭症之间存在共同联系。