FGF-Dependent Formation of Commissures in the CNS

描述(申请人提供)：为了在动物的环境中发挥作用，动物的中枢神经系统(CNS)的左右两侧需要交换信息。这项R21研究计划的最终目的是了解连接CNS两侧的连合是如何形成的，并为存在连合缺陷的人类疾病提供更好的洞察和治疗机会。为了让连合轴突从大脑或脊髓的一侧到达另一侧，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骤相互作用。尽管已经确定了连合轴突的关键寻路线索，但其他线索仍不清楚。此外，对于提供适当环境线索的细胞结构的诱导和模式，还有很多未知之处。例如，大脑两个半球由三个连合束连接，分别是胼胝体、海马体连合和前连合。尽管一些关键的轴突寻路分子已经被确定为形成大脑连合的关键分子，但关于是什么因素诱导了提供其中一些线索的专门化中线神经胶质结构，人们知之甚少。最近的证据表明，成纤维细胞生长因子信号可能参与了连合束的形成，但它在这一过程中的要求仍有待直接测试，其潜在作用的机制尚不清楚。在这里，我们使用条件遗传学方法来删除FGFR基因，我们测试了成纤维细胞生长因子信号在大脑半球和脊髓连合形成中的作用，并阐明了成纤维细胞生长因子信号作用的机制。

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.