Disorders of forebrain development have been implicated in the etiology of psychiatric illnesses including autism and schizophrenia. Previous studies have shown that homeobox genes Dlx and Emx are expressed in restricted domains of the mouse forebrain (the basal forebrain and cortex, respectively) during periods of neurogenesis, migration, and differentiation. This proposal tests two hypotheses: (1) that Dlx genes control phenotypic differentiation of the basal forebrain; (2) that Emx genes control phenotypic differentiation of the cortex. The hypotheses will be tested by gene targeting to alter Dlx and Emx expression in mice. The following approaches will be taken: (1) Null mutants of Dlx and Emx genes (generated previously) will be characterized phenotypically. (2) Re-specification of regional phenotypes will be attempted by ectopic expression of Dlx and Emx. (2a) To test whether ectopic expression of Dlx redirects cortical precursor cells to a basal forebrain phenotype, the Dlx-2 coding sequence will be placed under control of the Emx-1 promoter by gene substitution (""""""""knockin""""""""). (2b) To test whether ectopic expression of Emx redirects basal forebrain precursors to a cortical phenotype, the Emx-1 coding sequence will be placed under control of the Dlx-2 and Dlx-5 promoters. (3) The roles of these and related genes in normal and abnormal human brain development will be studied by northern blotting, in situ hybridization and immunohistochemistry of surgical and autopsy tissue specimens.
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