NOVEL FACTORS THAT REGULATE GNRH NEURONAL DEVELOPMENT

促性腺激素释放激素(GnRH)神经元呈现独特的模式 发育程序化的神经元迁移和基因表达。 它们起源于嗅觉定位，并迁移到前脑。 在胚胎发育过程中。控制这一点的机制 确切的迁徙时间模式是未知的；然而，紊乱 导致神经元迁移失败导致性功能障碍 成熟。研究促性腺激素释放激素合成调节的能力 促性腺激素释放激素产生细胞系GT1-7的研究进展 来源于前脑中迁移后的GnRH神经元，这些神经元 大量GnRH和Gn10细胞来源于移行的GnRH神经元 产生少量促性腺激素释放激素的嗅觉区。基于不同的表型 在两个GnRH产生细胞中，我们鉴定了不同的基因产物 在GnRH中表达 用分子生物学技术研究神经元的迁移和发育 差异显示聚合酶链式反应扩增。首字母 研究确定了10个唯一表达于 Gt1-7或Gn10神经细胞。克隆Gn8-01经鉴定为粘附型 Ark，一个新的受体酪氨酸家族的成员 其胞外结构域具有细胞黏附特性的激酶 分子。该基因在移行的Gn10细胞中表达，而不是 在迁移后的GT1-7细胞中。当被引入GT1-7细胞时，方舟 选择性抑制GnRH基因表达。初步研究表明 方舟和它的配体生长抑制特异性基因6(Gas6)， 在调节GnRH合成中发挥特定作用，保护 神经元迁移过程中的程序性细胞死亡和细胞-细胞接触。 这项提议将定义细胞和分子机制， 介导Ark在GnRH神经细胞中的作用。

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.