Embryonic Vascular Networks and GABA Neuron Migration

描述（由申请人提供）：gaba能中间神经元，出生在前脑腹侧（端脑）的远端萌发区，切向迁移到皮层，并采取其特定位置。调控这种迁移的细胞类型和分子线索仍有待阐明。我们已经确定了胚胎端脑中的两种内皮细胞（柱头细胞和心室周围细胞），每种细胞都具有不同的发育模式和转录因子表达。虽然远脑的脑髓血管在发育的最初阶段是神经管周围神经丛的衍生物，但脑室周围血管网络以有序的腹侧到背侧梯度发育，并在gaba能中间神经元迁移一天之前进入远脑背侧。我们的初步研究表明，胚胎端脑的心室周围血管网络在空间和时间上都处于良好的位置，可以影响gaba能中间神经元从基底端脑向背端脑的迁移。本应用将检验脑脊液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能的中间神经元在脑背壁形成两个空间上不同的流，一个紧挨着脑脊液网络，另一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、全载和免疫组织化学技术来检查心室周围血管网络是否为中间神经元的迁移提供了支架。在特定目的2A和2B中，我们将通过体外移植和细胞迁移实验来测试脑膜内皮细胞或脑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指导线索。此外，在特定的目标2C中，将通过微阵列分析脑膜内皮细胞、脑室周围内皮细胞和皮质gaba能中间神经元的基因表达谱，以确定这些细胞类型之间的新交叉对话。研究结果可能对整个发育中的中枢神经系统血管生成和神经元迁移的调控概念和机制产生深远影响。公共卫生相关性：这里提出的研究将为神经迁移的分子控制提供新的见解，并将对理解皮层发育畸形（MCD）具有重要意义，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.