DEVELOPMENTAL CONTROL OF GNRH EXPRESSION BY POU PROTEINS

描述（改编自研究者摘要）：POU同源结构域 蛋白质是在分化中起作用的转录因子，并且 神经内分泌基因的发育控制。 GnRH基因是 在下丘脑神经元的子集中表达，并且在其 其表型在发育过程中的可塑性。 GnRH神经元表型是 当细胞完成早期增殖时， 胚胎发生，然后在发情期间经历损失和恢复 周期 这就引出了一个问题，POU蛋白是否在细胞凋亡中起作用。 控制神经元GnRH基因表达。 POU域家族成员， SCIP和Brn-4是从GT 1 -7神经元细胞克隆的。 生理 通过SCIP或Brn-4与GnRH的共定位， 体内神经元 SCIP和Brn-4的过量产生显示出抑制或 分别激活GnRH启动子活性，需要直接结合 DNA和蛋白质之间的相互作用。 该提案有四个具体目标： 目的1-研究SCIP和Brn-4在体内GnRH神经元中的表达; 目的2-确定通过靶向的促性腺激素释放激素（GnRH）的SCIP调节的相关性。 SCIP在转基因动物中过表达和拮抗作用; 定位GnRH启动子的顺式作用元件， SCIP的抑制和Brn-4及其蛋白伴侣的激活; 4-鉴定和克隆指导SCIP和Brn-4作用的蛋白质配偶体 关于GnRH 这些研究将共同确定生理作用， POU蛋白控制和GnRH基因表达的细胞机制。

DESCRIPTION (Adapted from the Investigator's Abstract): POU homeodomain proteins are transcription factors that play a role in differentiation, and the developmental control of neuroendocrine genes. The GnRH gene is expressed in a subset of hypothalamic neurons and is unique in its plasticity of its phenotype across development. GnRH neuronal phenotype is acquired rapidly as cells complete an early proliferation during embryogenesis, and then undergo loss and reinstatement during the estrous cycle. This led to the question whether POU proteins play a role in the control of neuronal GnRH gene expression. The POU-domain family members, SCIP and Brn-4 were cloned from GT1-7 neuronal cells. Physiological significance was shown by colocalization of SCIP or Brn-4 with GnRH in neurons in vivo. Overproduction of SCIP and Brn-4 was shown to repress or activate GnRH promoter activity, respectively, requiring both direct binding to DNA and protein-protein interactions. This proposal has 4 specific aims: Aim 1-To assess the expression of SCIP and Brn-4 in GnRH neurons in vivo; Aim 2-define the relevance of SCIP modulation of GnRH by targeted overexpression and antagonism of SCIP in transgenic animal; Aim 3-precisely localize the cis-acting elements of the GnRH promoter that mediate repression by SCIP and activation by Brn-4 and their protein partners; 4-identify and clone the protein partners that direct SCIP and Brn-4 action on GnRH. Together these studies will define the physiological role and cellular mechanisms of POU protein control and GnRH gene expression.