Embryonic Vascular Networks and GABA Neuron Migration

描述（由申请人提供）：GABA能中间神经元，出生于腹侧前脑（端脑）的远程萌发区，切向迁移到皮质中，以占据其特定位置。调节这种迁移的细胞类型和分子线索仍有待阐明。我们已经确定了两个人口的内皮细胞（软膜和脑室周围）在胚胎端脑，每一个不同的发展模式和转录因子的表达。虽然端脑的软脑膜血管是从发育的最早阶段开始围绕神经管的神经丛的衍生物，但室周血管网络以有序的腹侧到背侧梯度发育，并在GABA能中间神经元迁移前一天进入背侧端脑。我们的初步研究表明，脑室周围血管网络在胚胎端脑的空间和时间定位良好，影响GABA能中间神经元从基底端脑背侧的迁移。本申请将检查软膜和脑室周围血管网络是否独立调节GABA能中间神经元向特定皮质区域的迁移和分选。GABA能中间神经元在背侧大脑壁中形成两个空间上不同的流，一个紧邻软膜网络，第二个被脑室周围网络包围。在具体目标1中，我们将通过延时成像、整体切片和免疫组织化学技术来检查室周血管网络是否为中间神经元的迁移提供了支架。在具体目标2A和2B中，我们将通过体外移植和细胞迁移测定来测试软脑膜内皮细胞或心室周围内皮细胞是否在GABA能中间神经元的迁移中提供不同的引导线索。此外，在具体目标2C中，将通过微阵列分析软脑膜内皮细胞、室周内皮细胞和皮质GABA能中间神经元的基因表达谱，以鉴定这些细胞类型之间的新的交叉作用。结果可能对整个发育中的CNS的血管生成和神经元迁移的调节的概念和机制产生深远的影响。公共卫生相关性：本文提出的研究将为神经迁移的分子控制提供新的见解，并将对理解皮质发育畸形（MCD）产生影响，这是几种神经系统疾病的形态学和生理学基础。

DESCRIPTION (provided by applicant): GABAergic interneurons, born in remote germinative zones in the ventral forebrain (telencephalon) migrate tangentially into the cortex to adopt their specific positions. The cell types and molecular cues that regulate this migration remain to be elucidated. We have identified two populations of endothelial cells (pial and periventricular) in the embryonic telencephalon, each with distinct developmental patterns and transcription factor expression. While the pial vessels of the telencephalon are derivatives of the perineural plexuses surrounding the neural tube from the earliest stages of development, the periventricular vessel network develops in an orderly ventral to dorsal gradient, and enters the dorsal telecephalon a day prior to migration of GABAergic interneurons. Our preliminary studies show that the periventricular vessel network in the embryonic telencephalon is spatially and temporally well positioned to influence migration of GABAergic interneurons from the basal to the dorsal telencephalon. This application will examine whether the pial and periventricular vessel networks independently regulate migration and sorting of GABAergic interneurons to specific cortical regions. GABAergic interneurons form two spatially distinct streams in the dorsal cerebral wall, one that is immediately adjacent to the pial network and the second that is enwrapped by the periventricular network. In specific aim 1, we will examine if the periventricular vessel network provides a scaffold for migration of the interneurons by time-lapse imaging, whole mounts and immunohistochemistry techniques. In specific aims 2A and 2B, we will test if either the pial endothelial cells or periventricular endothelial cells provide distinct guidance cues in the migration of GABAergic interneurons by in vitro transplantation and cell migration assays. In addition, in specific aim 2C, gene expression profiles of pial endothelial cells, periventricular endothelial cells and cortical GABAergic interneurons will be analyzed by microarrays to identify novel cross-talks between these cell types. Results could have far-reaching effects on concepts and mechanisms of regulation of angiogenesis and neuronal migration throughout the developing CNS. PUBLIC HEALTH RELEVANCE: The studies proposed here will offer novel insights into the molecular control of neural migration and will have implications for understanding malformations of cortical development (MCD) which is the morphological and physiological basis of several neurological diseases.