NOVEL FACTORS THAT REGULATE GNRH NEURONAL DEVELOPMENT

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Gonadotropin releasing hormone (GnRH) neurons display a unique pattern of a developmentally programmed neuronal migration and gene expression. They originate in the olfactory placode and migrate to the forebrain during embryologic development. The mechanisms that control this precisely timed pattern of migration are unknown; however, disorders that result in failure of neuronal migration cause defects in sexual maturation. The ability to study the regulation of GnRH synthesis was advanced with the development of GnRH producing cell lines: GT1-7 cells derived from postmigratory GnRH neurons in the forebrain that make abundant GnRH, and Gn10 cells derived from migratory GnRH neurons in the olfactory area that make little GnRH. Based on the different phenotype of the two GnRH producing cells, we identified gene products divergently expressed across GnRH neuronal migration and development using the molecular technique of differential display polymerase chain reaction amplification. Initial studies identified ten cDNA clones uniquely expressed in either the GT1-7 or Gn10 neuronal cells. Clone Gn8-01 was identified as "adhesion related kinase", Ark, a member of a novel family of receptor tyrosine kinases, whose extracellular domain has features of a cell adhesion molecule. This cDNA is expressed in the migratory Gn10 cells and not in the postmigratory GT1-7 cells. When introduced into GT1-7 cells, Ark selectively represses GnRH gene expression. Preliminary studies suggest that Ark together with its ligand, growth arrest specific gene 6 (Gas6), play specific roles in modulation of GnRH synthesis, protection from programmed cell death and cell-cell contact during neuronal migration. This proposal will define the cellular and molecular mechanisms that mediate Ark's action in GnRH neuronal cells.