FGF-Dependent Formation of Commissures in the CNS

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DESCRIPTION (provided by applicant): To function in its environment, the left and right sides of an animal's central nervous system (CNS) need to exchange information. The ultimate goal of this R21 research proposal is to understand how the commissures, the axonal tracts which connect both sides of the CNS, are formed and to provide better insight and treatment opportunities for human disorders in which there are commissural defects. For commissural axons to find their way from one side of the brain or spinal cord to the other, several key developmental events must occur, including the early patterning of the axonal environments and the multistep interaction of axons with pathfinding cues. Although key pathfinding cues have been identified for commissural axons, others remain unknown. In addition, much is unknown about what induces and patterns the cellular structures that provide the appropriate environmental cues. For example, the cerebral hemispheres are connected by three commissural tracts, the corpus callosum, the hippocampal commissure, and the anterior commissure. Although a few key axon pathfinding molecules have been identified as essential in forming the cerebral commissures, little is known about what factors induce the specialized midline glial structures that provide some of these cues. Recent evidence suggest that Fibroblast Growth Factor (FGF) signaling may be involved in forming commissural tracts, but its requirement in this process remains to be directly tested and the mechanism underlying its putative role is unknown. Here, using a conditional genetic approach to delete Fgfr genes, we test the role of FGF signaling in forming commissures in the cerebral hemispheres and spinal cord and elucidate the mechanisms by which FGF signaling acts.