Defining common molecular pathways in cortical interneuron migration and vascular development

在人类中，大脑皮层是目前为止大脑中包含大部分神经元的最重要的部分。在哺乳动物中，神经元被分为两大类，兴奋性锥体神经元投射到皮质外的区域，以及非锥体细胞，含有GABA的皮质中间神经元。这些细胞类型在不同的生发区产生，并遵循不同的迁移方式到达它们在皮质中的最终位置：径向和切向。所有锥体神经元都产生于胚胎皮质的脑室区，并在胶质纤维的支持下沿放射状(即垂直于大脑表面)迁移(亲胶质迁移)。中间神经元出现在神经节隆起，这是基底端脑中形成基底节的一个区域。这些细胞沿着漫长而曲折的路线积极迁移到发育中的皮质中。一旦进入皮质，它们就会沿着两条主切向(即与软膜表面平行)的迁移流之一，然后径向转向，到达它们在发育中的皮质板中的位置。据认为，这些细胞使用皮质分离轴突从基底端脑到皮质(神经亲性迁移)和放射状胶质细胞在皮质板内旅行的最后部分(亲胶质迁移)。然而，最近出现的证据支持亲血管迁移模式，即中间神经元使用发育中的血管网络作为其运动的底物。在这里，我们建议检验一种假设，即由血管系统分泌的各种趋化因子调节中间神经元的发育和迁移。具体地说，我们建议将小鼠遗传工具与细胞和分子生物学技术相结合，以研究血管分泌分子在皮质中间神经元的生成、存活和迁移中的作用。我们将重点关注血管内皮生长因子(VEGF)，特别关注这种血管生成因子在这些发育事件中发挥作用的分子机制。除了研究血管内皮生长因子在皮质间神经元迁移中的作用外，我们还希望评估这一因素和其他血管分泌因素是否决定了皮质间神经元迁移流的选择。拟议的研究计划将探索切向神经元迁移的新机制，并加强我们对大脑这一区域发育障碍的病因的理解，如智力低下、自闭症和某些形式的癫痫。

In man, the cerebral cortex is by far the most important part of the brain containing the majority of its neurons. In mammals, neurons are divided into two broad classes, the excitatory pyramidal neurons that project to areas outside the cortex, and the nonpyramidal cells, the GABA-containing cortical interneurons. These cell types are generated in different germinal zones and follow distinct modes of migration to reach their final positions in the cortex: radial and tangential. All pyramidal neurons are generated in the ventricular zone of the embryonic cortex and migrate radially (i.e. perpendicular to the surface of the brain) using the support of glial fibres (gliophilic migration). Interneurons arise in the ganglionic eminence, an area in the basal telencephalon that gives rise to the basal ganglia. These cells follow long and tortuous routes to actively migrate into the developing cortex. Once in the cortex, they follow one of two main tangential (i.e. parallel to the pial surface) migratory streams before they turn radially to reach their positions in the developing cortical plate. It is thought that these cells use corticofugal axons to navigate from the basal telencephalon to the cortex (neurophilic migration) and radial glia in their final part of their journey within the cortical plate (gliophilic migration). However, evidence has recently emerged to support vasophilic mode of migration, where interneurons use the developing vascular network as a substrate for their movement. Here, we propose to test the hypothesis that various chemotropic factors, secreted by the vasculature, regulate the development and migration of interneurons. Specifically, we propose to combine mouse genetic tools with cell and molecular biological techniques to investigate the roles of blood vessel secreted molecules on the generation, survival and migration of cortical interneurons. We shall focus on vascular endothelial growth factor (VEGF), paying particular attention to the molecular mechanisms through which this angiogenic factor exerts its function in these developmental events. In addition to studying the role of VEGF in cortical interneuron migration, we wish to assess whether this and other blood vessel secreted factors dictate the choice of migratory stream by cortical interneurons. The proposed research programme will explore novel mechanisms in tangential neuronal migration, and enhance our understanding of the aetiologies of developmental disorders of this area of the brain such as mental retardation, autism and certain forms of epilepsy.