Defining common molecular pathways in cortical interneuron migration and vascular development

定义皮质中间神经元迁移和血管发育的常见分子途径

• 批准号: BB/M009424/1
• 负责人: John Parnavelas
• 金额: $ 75.45万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM009424%2F1
• 关键词: Defining; common; molecular; pathways; cortical

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.

在人类中，大脑皮层是迄今为止大脑中最重要的部分，包含大部分神经元。在哺乳动物中，神经元分为两大类，兴奋性锥体神经元投射到皮质外的区域，非锥体细胞，含有GABA的皮质中间神经元。这些细胞类型产生于不同的生发区，并遵循不同的迁移模式到达其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，并利用胶质纤维的支持径向迁移（即垂直于大脑表面）（亲胶质迁移）。中间神经元产生于神经节隆起，这是基底端脑中产生基底神经节的区域。这些细胞沿着漫长而曲折的路线积极迁移到发育中的皮层。一旦进入皮质，它们在径向转向到达发育中的皮质板中的位置之前遵循两个主要切线（即平行于软膜表面）迁移流之一。据认为，这些细胞使用离皮质轴突从基底端脑导航到皮质（嗜神经细胞迁移）和放射状胶质细胞在其在皮质板内的旅程的最后部分（嗜胶质细胞迁移）。然而，最近出现的证据支持亲血管的迁移模式，其中中间神经元使用发育中的血管网络作为其运动的基质。在这里，我们建议测试的假设，各种趋化因子，分泌的血管，调节中间神经元的发育和迁移。具体而言，我们建议将联合收割机小鼠遗传工具与细胞和分子生物学技术相结合，研究血管分泌分子对皮质中间神经元的产生、存活和迁移的作用。我们将集中在血管内皮生长因子（VEGF），特别注意的分子机制，通过这种血管生成因子发挥其功能，在这些发展的事件。除了研究VEGF在皮层中间神经元迁移中的作用外，我们还希望评估这一点和其他血管分泌因子是否决定皮层中间神经元迁移流的选择。建议的研究计划将探讨切线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（如智力迟钝、自闭症和某些形式的癫痫）的病因的了解。

项目成果

Semaphorin3A-neuropilin1 signalling is involved in the generation of cortical interneurons.

• DOI: 10.1007/s00429-016-1337-3
• 发表时间: 2017-07
• 期刊: Brain structure & function
• 影响因子: 3.1
• 作者: Andrews WD;Barber M;Nemitz M;Memi F;Parnavelas JG
• 通讯作者: Parnavelas JG

Vascular-Derived Vegfa Promotes Cortical Interneuron Migration and Proximity to the Vasculature in the Developing Forebrain.

• DOI: 10.1093/cercor/bhy082
• 发表时间: 2018-07-01
• 期刊: Cerebral cortex (New York, N.Y. : 1991)
• 作者: Barber M;Andrews WD;Memi F;Gardener P;Ciantar D;Tata M;Ruhrberg C;Parnavelas JG
• 通讯作者: Parnavelas JG

Protective role of Cadherin 13 in interneuron development.

• DOI: 10.1007/s00429-017-1418-y
• 发表时间: 2017-11
• 期刊: Brain structure & function
• 影响因子: 3.1
• 作者: Killen AC;Barber M;Paulin JJW;Ranscht B;Parnavelas JG;Andrews WD
• 通讯作者: Andrews WD

Tissue-specific miRNA Expression Profiling in Mouse Heart Sections Using In Situ Hybridization.

• DOI: 10.3791/57920
• 发表时间: 2018-09
• 期刊: Journal of visualized experiments : JoVE
• 作者: F. Memi;D. Tirziu;I. Papangeli

Cadherin 8 regulates proliferation of cortical interneuron progenitors.

• DOI: 10.1007/s00429-018-1772-4
• 发表时间: 2019-01
• 期刊: Brain structure & function
• 影响因子: 3.1
• 作者: Memi F;Killen AC;Barber M;Parnavelas JG;Andrews WD
• 通讯作者: Andrews WD