Fgf8 Function in Midbrain/r1 Borders and Patterning

描述（由申请人提供）：我们理解哺乳动物发育的基础是如何建立和解释空间线索的问题。中脑/后脑区域已经成为研究中枢神经系统中组织者驱动的发育的范例，因为表达分泌因子Fgf 8的位于中央的组织中心（峡部）使中脑和产生小脑的前后脑的前/后轴图案化。大脑进化的关键是，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。了解这些区域通常如何发育对于我们理解相关的先天性和神经退行性疾病至关重要。发育的基本知识可以导致疾病预防和基于细胞的治疗。我们已经表明，大脑的模式化始于将神经板分成单独的Otx2和Gbx2结构域。然后在Otx2/Gbx2交界处（谱系边界）诱导Fgf8。Fgf8的2种同种型以及Fgf17/18然后差异诱导中脑和小脑。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是否足以促进中脑/后脑发育？FGF17的作用是什么？3. FGF8在中脑和小脑发育中什么时候需要？4. Fgf 8是否通过设置梯度直接诱导中脑和后脑沿着前后轴的不同结构？5.是否需要Fgf8或Wnt 1信号来维持区室边界？

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?