Mechanisms of Neocortical Development Regulated by Tbr1

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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.