Mechanisms of Neocortical Development Regulated by Tbr1

描述（由申请人提供）：皮质发育畸形是癫痫、智力迟钝、自闭症和相关神经系统疾病的主要原因。畸形源于皮质细胞迁移、轴突束形成和分化的缺陷。这些基本的过程分别是在皮层中产生特征层流结构、精确的神经回路和专门的神经元类型所必需的。Tbr1是一种t结构域转录因子，在新皮层（皮层的最大部分）的基本发育过程中是必需的。Tbr1缺陷小鼠有严重的迁移障碍（类似于人类无脑畸形的一种形式），以及轴突寻路缺陷（影响胼胝体、皮质脊髓、皮质丘脑和丘脑皮质投射）和神经元分化。该项目的主要目标是通过研究Tbr1的作用来阐明皮层发育的潜在机制。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是明确Tbr1在皮质细胞迁移中的作用。这将通过移植研究来完成。目的2是确定Tbr1在皮质丘脑和丘脑皮质轴突连接形成中的作用。使用一种新的体外实验，我们将确定Tbr1是否调节皮质和丘脑轴突反应，引导线索，或两者兼而有之。此外，通过在胚胎中过表达Tbr1，我们将确定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类特异性命运选择中的作用。功能获得试验将用于确定Tbr1是否诱导谷氨酸能分化，抑制gaba能分化，以及（在高水平上）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.