Fgf8 Function in Midbrain/r1 Borders and Patterning

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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?