FGF-Dependent Formation of Commissures in the CNS

描述（由申请人提供）：为了在其环境中发挥作用，动物中枢神经系统（CNS）的左侧和右侧需要交换信息。这项R21研究提案的最终目标是了解连合（连接CNS两侧的轴突束）是如何形成的，并为存在连合缺陷的人类疾病提供更好的见解和治疗机会。为了让连合轴突找到从大脑或脊髓一侧到另一侧的路径，必须发生几个关键的发育事件，包括轴突环境的早期模式以及轴突与寻路线索的多步相互作用。虽然连合轴突的关键寻路线索已经确定，其他仍然未知。此外，关于是什么诱导和模式的细胞结构，提供适当的环境线索，很多是未知的。例如，大脑半球由三个连合束连接，即胼胝体、海马连合和前连合。虽然一些关键的轴突寻路分子已被确定为形成脑连合必不可少的，很少有人知道是什么因素诱导专门的中线胶质结构，提供这些线索。最近的证据表明，成纤维细胞生长因子（FGF）信号可能参与形成连合束，但其在这一过程中的要求仍有待直接测试，其潜在的作用机制是未知的。在这里，使用条件遗传学方法删除FGFR基因，我们测试的作用，FGF信号形成连合在大脑半球和脊髓，并阐明FGF信号的作用机制。

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.