Fgf8 Function in Midbrain/r1 Borders and Patterning

描述（由申请人提供）：我们对哺乳动物发育的理解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组织者驱动发育的一个范例，因为位于中心的组织中心（峡部）表达分泌因子Fgf8，它决定了产生小脑的中脑和后脑前轴/后轴。作为大脑进化的关键，组织者的位置最终决定了中脑和小脑的相对大小，它们控制着人类的许多基本行为。了解这些区域如何正常发育对我们理解相关的先天性和神经退行性疾病至关重要。对发育的基本了解可能会导致疾病预防和基于细胞的治疗。我们已经证明，大脑的模式开始于神经板分裂成单独的Otx2和Gbx2区域。然后，Fgf8在Otx2/Gbx2交界处（一个谱系边界）被诱导。Fgf8的2个亚型以及Fgf17/18分别诱导中脑和小脑。我们建议以这一知识框架为基础，解决以下关键问题。1. 地峡组织者细胞的最终命运是什么？2. Fgf8a或Fgf8b对中脑/后脑发育是否足够？ Fgf17的作用是什么？3. 什么时候中脑和小脑发育需要Fgf8 ？4. Fgf8是否通过设置Fgf蛋白梯度直接沿前/后轴诱导不同的中脑和后脑结构？5. 是否需要Fgf8或Wnt1信号来维持隔室边界？

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?