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，动物的左右中枢神经系统（CNS）需要交换信息。这项R21研究计划的最终目标是了解连接中枢神经系统两侧的轴突束是如何形成的，并为存在连接缺陷的人类疾病提供更好的见解和治疗机会。交联轴突要从大脑或脊髓的一侧找到通往另一侧的路，必须发生几个关键的发育事件，包括轴突环境的早期模式和轴突与寻径线索的多步骤相互作用。虽然已经确定了交联轴突的关键寻路线索，但其他线索仍然未知。此外，是什么诱导和模式细胞结构，提供适当的环境线索，是未知的。例如，大脑半球由三个联合束连接，胼胝体、海马联合和前联合。虽然一些关键的轴突寻路分子已被确定为形成大脑连接的必要因素，但对于什么因素诱导提供这些线索的特化中线胶质结构知之甚少。最近的证据表明，成纤维细胞生长因子（FGF）信号可能参与了交束的形成，但其在这一过程中的需求仍有待直接测试，其推测作用的机制尚不清楚。在这里，我们使用一种条件遗传方法来删除Fgfr基因，我们测试了FGF信号在大脑半球和脊髓形成通讯中的作用，并阐明了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.