Pathogenesis of Tuberous Sclerosis Cortical Lesions

描述(由申请人提供)： 在皮质发生过程中，放射状胶质细胞及其后代经历了刻板的分裂和迁移模式，以协调神经元的产生和放置，创造出分层的大脑皮层。相反，结节性硬化症基因杂合子TSC1或TSC2杂合子个体大脑中的致痫皮质病变是超细胞的，显示出破坏的板层和扭曲的灰白质边界。这些畸形被认为是由来自前体的克隆组成，在这些克隆中，第二次突变消除了任何一种基因产物的表达。然而，这些皮质损伤与正常的皮质增殖和迁移模式相关的发病机制尚未被研究，TSC基因产物在皮质生成中的作用仍不清楚。下面概述的实验建议通过在体内模拟结节性硬化症的遗传缺陷来解决这些问题。靶向TSC2转录本的RNAi载体将通过宫内注射到大鼠胚胎侧脑室的方式导入皮质祖细胞。通过观察这些标记细胞与对照组相比的增殖和迁移情况，将检测基因缺陷对皮质生成的影响。

DESCRIPTION (provided by applicant): During corticogenesis, radial glial cells and their progeny undergo stereotyped patterns of division and migration that coordinate neuronal production and placement, creating the layered cerebral cortex. In contrast, epileptogenic cortical lesions in the brains of individuals heterozygous for a tuberous sclerosis gene, TSC1 orTSC2, are hypercellular and display disrupted lamination and distorted gray-white matter boundaries. These malformations are thought to consist of clones derived from precursors in which a secondary mutation eliminates expression of either gene product. However, the pathogenesis of these cortical lesions in relation to normal patterns of cortical proliferation and migration has not been investigated, and the role of TSC gene products in corticogenesis remains unknown. Experiments outlined below propose to address these questions by mimicking the genetic deficiency of tuberous sclerosis in vivo. RNAi vectors targeting TSC2 transcript will be introduced into cortical progenitors through intrauterine injections into lateral ventricles of rat embryos. By observing the proliferation and migration of these labeled cells in comparison to controls, the influence of the gene defect on corticogenesis will be examined.