Mechanisms of Neocortical Development Regulated by Tbr1

描述（由申请人提供）：皮质发育畸形是癫痫、精神发育迟滞、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。这些基本过程是必要的，以产生特有的层状结构，精确的神经回路，并在皮层专门的神经元类型，分别。Tbr 1是一种T结构域转录因子，对于新皮质（皮质的最大部分）中的基本发育过程是必需的。tbr 1缺陷小鼠有严重的迁移障碍（类似于人类无脑回畸形的一种形式），以及轴突寻路（影响胼胝体、皮质脊髓、皮质丘脑和丘脑皮质投射）和神经元分化的缺陷。该项目的主要目标是通过研究Tbr 1的作用来阐明皮质发育的潜在机制。我们的假设假定，Tbr 1调节特定方面的mammatergic神经元迁移，轴突寻路和分化。该项目有三个具体目标。目的1是确定Tbr 1在皮质细胞迁移中的作用。这将通过移植研究来实现。目的二是明确Tbr 1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Tbr 1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，通过在胚胎中过表达Tbr 1，我们将解决Tbr 1是否自主指定皮层轴突连接细胞。目的3是确定Tbr 1在胚胎分化和层特异性命运选择中的作用。将使用功能获得试验来确定Tbr 1是否诱导谷氨酸能分化、抑制GABA能分化和（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.