Molecular Mechanisms of Cerebral Cortical Patterning

大脑皮层模式的分子机制

• 批准号: 9110331
• 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/9110331
• 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 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; 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（由申请人提供）：拟议研究的长期目标是了解启动哺乳动物大脑皮层发展的机制，以及新皮层区域图的控制形成。发现应与源于大脑皮层发育缺陷的一系列人类疾病有关。该提案具有三个目标，基于证据表明，信号分子成纤维细胞生长因子（FGF）8在胚胎小鼠新皮质原基（NP）中充当分级形态​​，并启动遗传级联反应，从而导致区域图的形成。令人惊讶的是，NP中的异位FGF8可以诱导重复的区域，甚至可以诱导复杂的地图。 AIM 1建立在以前的系统搜索FGF8下游的候选基因的基础上，而在级联的下游，这会导致皮质区域化。我们使用深层测序（RNA-SEQ）比较了NP组织的转录组，在不同的时间表上暴露于不同浓度的FGF8，模仿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在NP中具有区域表达，并与其他地方的胚胎图案链接。我们将使用小鼠遗传学和子宫微异化中的基因转移到活着的小鼠胚胎中，以确定糖基因在图案构图区域图中的作用。 AIM 2将研究FGF8如何与FGF受体（FGFR）相互作用，以及潜在的内源性FGFR抑制剂和增强子如何控制FGF8 Grandient，并因此如何发展区域图。 AIM 3将研究嗅球原基（OBP），作为确定胚胎皮层中有界区域的有前途模型系统。在任何新皮层区域之前，OBP是一个独特的有限域。我们有证据表明，FGF8可以诱导次级OBP，并将在此目标中进一步研究FGF8诱导OBP。 OBP是从紧邻前额叶皮层区域附近的组织得出的。实验将探讨这些不同的皮质结构如何在发育中彼此之间分离。我们实验的部分动机是嗅觉缺陷与精神分裂症和自闭症之间的共同联系的主张。