Mechanisms of Neocortical Development Regulated by Tbr1

描述(申请人提供)：皮质发育畸形是癫痫、智力低下、自闭症和相关神经疾病的主要原因。畸形是由皮质细胞迁移、轴索形成和分化缺陷引起的。这些基本过程是分别在大脑皮层中产生特有的层状结构、精确的神经回路和特殊的神经元类型所必需的。Tbr1是一种T结构域转录因子，在新皮质(皮质的最大部分)的基本发育过程中是必需的。Tbr1基因缺陷小鼠有严重的迁徙障碍(类似于人类无脑畸形)，以及轴突寻路缺陷(影响膝盖骨、皮质脊髓、皮质丘脑和丘脑皮质投射)和神经元分化。这个项目的主要目标是通过研究Tbr1的作用来阐明皮质发育的潜在机制。我们的假设假设Tbr1调节谷氨酸能神经元迁移、轴突寻路和分化的特定方面。这个项目有三个具体目标。目的1确定Tbr1在大脑皮层细胞迁移中的作用。这将通过移植研究来实现。目的2确定Tbr1在皮质丘脑和丘脑皮质轴突连接形成中的作用。使用一种新的体外试验，我们将确定Tbr1是否调节皮质和丘脑轴突反应，指导线索，或两者兼而有之。此外，通过在胚胎中过度表达Tbr1，我们将解决Tbr1是否自主地指定皮质轴突连接细胞。目的3是确定Tbr1在谷氨酸能分化和蛋鸡特定命运选择中的作用。功能增益分析将被用来确定Tbr1是否诱导谷氨酸能分化，抑制GABA能分化，以及(在高水平)诱导深层神经元类型的表型。

DESCRIPTION (provided by applicant): Malformations of cortical development are a major cause of epilepsy, mental retardation, autism, and related neurological disorders. Malformations arise from defects of cortical cell migration, axon tract formation, and differentiation. These fundamental processes are necessary to produce the characteristic laminar structure, precise neural circuitry, and specialized neuron types in the cortex, respectively. Tbr1 is a T-domain transcription factor that is necessary for fundamental developmental processes in the neocortex (the largest part of the cortex). Tbr1 deficient mice have a severe migration disorder (which resembles a form of human lissencephaly), as well as defects of axon pathfinding (affecting the callosal, corticospinal, corticothalamic, and thalamocortical projections) and neuronal differentiation. The broad goal of this project is to elucidate underlying mechanisms of cortical development by studying the role of Tbr1. Our hypotheses postulate that Tbr1 regulates specific aspects of glutamatergic neuron migration, axon pathfinding, and differentiation. This project has three specific aims. Aim 1 is to define the role of Tbr1 in cortical cell migration. This will be accomplished by transplantation studies. Aim 2 is to define the role of Tbr1 in formation of corticothalamic and thalamocortical axon connections. Using a novel in vitro assay, we will determine if Tbr1 regulates cortical and thalamic axon responses, guidance cues, or both. Also, by overexpressing Tbr1 in embryos, we will resolve whether Tbr1 specifies cortical axon connections cell autonomously. Aim 3 is to define the role of Tbr1 in glutamatergic differentiation and layer-specific fate choices. Gain-of-function assays will be used to determine if Tbr1 induces glutamatergic differentiation, suppresses GABAergic differentiation, and (at high levels) induces phenotypes of deep-layer neuron types.