Human neurological disorders, such as mental retardation, cerebral palsy and some forms of epilepsy are usually caused by abnormalities in development of the brain. The goal of the research described in this grant application is to begin to understand some of the genetic mechanisms that control development of the cerebral cortex, which is the largest component of the human brain. The hypothesis behind these experiments is that regional specification of, and, the differentiation within the cerebral cortex, is in part controlled by transcriptional regulators whose expression and function is independent of synaptic influences. Candidates for several of the genes that participate in this regulatory network have recently been identified by this research group as well as by scientists in several other laboratories. Many of these candidate genes encode proteins containing a homeodomain. These genes include members of the Otx and Emx families. Recently, a novel candidate transcription factor was discovered, related to the Brachyury gene, that is named Tbr-1. The work proposed in this application will focus on the role of the Tbr-1 and Emx-1 genes in the development of the cerebral cortex. The work is divided into three parts: (A) Structural analysis of the Tbr-1, Tbr-2 and Emx-1 genes; (B) An analysis of the organization of the cerebral cortex in the embryonic, fetal and postnatal mouse, by studying the expression patterns of Tbr-1, Tbr-2, Emx-1 and other genes; (C) Functional analysis of the Tbr-1, Tbr-2 and Emx-1 genes by making null alleles using gene replacement methods.
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