利用斑马鱼模型研究分泌粒蛋白II在GnRH3神经元迁移和增殖中的功能

促性腺激素释放激素（GnRH）神经元对于脊椎动物青春期启动至关重要，GnRH神经元发育缺陷会引起低促性腺激素型性腺功能减退症，发掘新的GnRH神经元发育调控因子有重要价值。申请人基于前期的研究结果和文献调研分析，提出科学假设：分泌粒蛋白II（SgII）是调控GnRH3神经元迁移和增殖的新因子。本项目拟通过构建sgIIa启动子驱动荧光表达的转基因斑马鱼，详细分析sgIIa阳性细胞与GnRH3神经元共分布特征；构建sgIIa突变且GnRH3神经元带有荧光标记的斑马鱼家系，分析sgIIa缺失对GnRH3神经元迁移及增殖的影响，揭示sgIIa调控GnRH3神经元发育的功能；进一步分析sgIIa调控GnRH3神经元发育与PI3K/Akt信号通路的关系，阐明其作用机制，为揭示人类低促性腺激素型性腺功能减退症的致病机理提供理论指导。

Gonadotropin-releasing hormone (GnRH) neuronal system is essential for the initiation of puberty in vertebrates. Developmental defects of GnRH neurons result in hypogonadotropic hypogonadism. Discovering new genes that regulate GnRH neuron development is important for elucidating the pathogenesis of hypogonadotrophic hypogonadism. Based on previous research results of GnRH neuron and literature searching, the applicant hypothesized that Secretogranin II (SgII) is a novel factor which plays a critical role in GnRH3 neuron migration and proliferation. Co-distribution characteristics of sgIIa-positive cells and GnRH3 neurons will be studied through constructing transgenic zebrafish model. On the basis of cell co-distribution studies, the role of sgIIa in GnRH3 neuron migration and proliferation will be investigated through constructing sgIIa-/-zebrafish lines. After revealing the role of sgIIa in regulating GnRH3 neuron development, the mechanism will be studied through analyzing the relationship between the role of sgIIa in GnRH3 neuron development and PI3K/Akt signaling pathway. Our study will provide theoretical guidance for revealing the pathogenesis of human hypogonadotrophic hypogonadism.