There is abundant evidence to suggest that neuropsychiatric disorders such as schizophrenia and autism are caused in many cases by genetic abnormalities that affect development and function of forebrain neural systems involved in cognition and emotion. The largest structures of the forebrain are the cerebral cortex and the striatum; both have been implicated as having a role in neuropsychiatric disorders. The goal of my research is to understand how genes regulate development of the striatum and other forebrain structures. To this end, my laboratory has studied the Dlx genes, which encode a family of homeodomain transcription factors. There are four known Dlx genes that are expressed in the embryonic forebrain. This application is for renewal of a grant in which I proposed to study the function of Dlx-1 and -2 using gene targeted mutagenesis in mice (1 R01 MH51561-01A1). We have accomplished the aims set out in that grant and have discovered that mice lacking both Dlx-1 and -2 have a severe abnormality of basal ganglia differentiation.
The aims of the experiments proposed in this grant application are focused on (1) fully characterizing the phenotype of the Dix-1, Dlx-2 and Dlx-1 and -2 mutant mice; (2) identifying and characterizing genes that are dysregulated in the Dlx-mutant mice; (3) studying the genetic interactions of the Dlx, Gsh and Mash genes; and (4) making mutations in Dlx-5, Dlx-6 and Dlx-5 and -6.
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