Fgf8 Function in Midbrain/r1 Borders and Patterning

Fgf8 在中脑/r1 边界和模式中的功能

• 批准号: 7232112
• 负责人: ALEXANDRA L. JOYNER
• 金额: $ 37.56万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7232112
• 关键词: Address; Alleles; Anterior; Behavior; Biological Assay; Border Crossings; Brain; Cell Death; Cell Therapy; Cells; Cerebellum; Cues; Development; Embryo; Evolution; Gene Expression; Gene Targeting; Genes; Genetic; Histology; Human; Knock-in Mouse; Knock-out; Knowledge; LacZ Genes; Lead; Maps; Midbrain structure; Neuraxis; Neurodegenerative Disorders; Pattern; Phenotype; Play; Positioning Attribute; Protein Isoforms; Proteins; Relative (related person); Reporter; Repression; Research Personnel; Role; Side; Signal Transduction; Structure; Tamoxifen; Time; cell type; disorder prevention; gain of function; hindbrain; mutant; neural plate; novel; programs; receptor function; size; transcription factor

DESCRIPTION (provided by applicant): Fundamental to our understanding of mammalian development is the question of how spatial cues are established and interpreted. The mid/hindbrain region has become a paradigm for studying organizer driven development in the central nervous system, since a centrally located organizing center (isthmus) that expresses the secreted factor Fgf8 patterns the anterior/posterior axes of the midbrain and anterior hindbrain that gives rise to the cerebellum. Key to evolution of the brain, the position of the organizer ultimately determines the relative size of the midbrain and cerebellum, which control many human basic behaviors. Understanding how these regions normally develop is critical to our understanding of related congenital and neurodegenerative diseases. A basic knowledge of development could lead to disease prevention and cell based therapies. We have shown that patterning of the brain begins with division of the neural plate into separate Otx2 and Gbx2 domains. Fgf8 is then induced at the Otx2/Gbx2 junction, a lineage border. 2 isoforms of Fgf8, as well as Fgf17/18 then differentially induce midbrain and cerebellum. We propose to build on this framework of knowledge and address the following key questions. 1. What is the ultimate fate of cells in the isthmic organizer? 2. Is Fgf8a or Fgf8b sufficient for mid/hindbrain development and what is the contribution of Fgf17? 3. When is Fgf8 required for midbrain and cerebellum development? 4. Does Fgf8 induces different midbrain and hindbrain structures along the anterior/posterior axis directly through setting up a gradient of Fgf proteins? 5. Is Fgf8 or Wnt1 signaling required to maintain compartment borders?

描述(申请人提供)：我们理解哺乳动物发育的基础是空间线索是如何建立和解释的问题。中脑/后脑区域已成为研究中枢神经系统组织者驱动发育的范例，因为表达分泌因子Fgf8的中央组织中心(峡部)排列在中脑和形成小脑的前后脑的前轴/后轴。大脑进化的关键，组织者的位置最终决定了控制人类许多基本行为的中脑和小脑的相对大小。了解这些区域是如何正常发育的，对于我们理解相关的先天性和神经退行性疾病至关重要。对发育的基本知识可以导致疾病预防和基于细胞的治疗。我们已经证明，大脑的模式始于将神经板划分为独立的OTX2和Gbx2区域。Fgf8随后在OTX2/Gbx2交界处被诱导，这是一个谱系边界。Fgf8的2个亚型和Fgf17/18分别诱导中脑和小脑。我们建议在这一知识框架的基础上，解决以下关键问题。1.峡部组织者中细胞的最终命运是什么？2.Fgf8a或Fgf8b对中/后脑的发育是否足够？3.中脑和小脑的发育何时需要Fgf8？4.Fgf8是否直接通过设置成纤维细胞生长因子蛋白的梯度而沿前后轴诱导不同的中脑和后脑结构？5.是否需要Fgf8或WNT1信号来维持脑室边界？