STEROID RECEPTORS AND CNS DEVELOPMENT

类固醇受体和中枢神经系统发育

• 批准号: 6046375
• 负责人: James W Truman
• 金额: $ 29.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6046375
• 关键词: DNA binding protein; Drosophilidae; Manduca; developmental genetics; developmental neurobiology; ecdysone; hormone regulation /control mechanism; juvenile hormones; mixed tissue /cell culture; molecular cloning; myoblasts; neurogenetics; neurons; protein isoforms; receptor binding; receptor expression; steroid hormone receptor; tissue mosaicism

DESCRIPTION (Abstract reproduced verbatim): The long term goals are to understand how steroid hormones regulate diverse patterns of development within the CNS. Studies on the insect models, Drosophila melonogaster and Manduca sexta, have shown that ecdysteroids can activate two discrete developmental programs depending on steroid concentration. Low steroid levels control tissue patterning and cellular determination while high steroid concentrations promote cell maturation. Ecdysteropid action is mediated through the ecdysone receptor (EcR) and its heterodimer partner ultraspiracle (USP). A mosaic analysis of clonal tissues that lacks USP suggests that the transcriptional silencing and transcriptional activation functions of the EcR/USP complex have different developmental functions; the former primarily mediating programs of tissue patterning and cell determination while the latter is involved in programs of cellular maturation. Insights gained about how these silencing and activational functions of the EcR/USP complex relate to developmental programs in these insect models will also be directly applicable to understanding homologous signaling systems in vertebrates -- those mediating the actions of thyroid hormone and the retinoids. Specific aims are: 1) determine the receptors and signaling molecules that cause the pre-metamorphic changes in Drosophila. 2) Use a mosaic analysis to determine the role of the ligand binding and DNA binding domains of EcR in mediating the two programs of developmental response. 3) Use the mosaic analysis of EcR mutants and the misexpression of EcR isoforms to examine the ability of each isoform to support patterning and determination processes versus maturational processes. 4) Use USP clones and in vitro challenges with ecdysteroids to examine how cell determination and cell maturation programs interact during development. 5) Utilize a neuron-myoblast coculture system to examine how neurons are able to direct the type of EcR isoform expressed in embryonic muscle and how receptor isoform choice relates to muscle growth and maturation responses.

描述（摘要逐字复制）：长期目标是 了解类固醇激素如何调节内部的各种发展模式 中枢神经系统。关于昆虫模型，果蝇Melonogaster和Manduca的研究 塞克斯塔（Sexta 程序取决于类固醇浓度。低类固醇水平控制组织 高级类固醇浓度促进图案和细胞测定 细胞成熟。通过ecdysone受体介导欧洲抗衰变作用 （ECR）及其异二聚体合作伙伴Ultraspiracle（USP）。马赛克分析 缺乏USP的克隆组织表明转录沉默和 ECR/USP复合物的转录激活功能具有不同的 发展功能；前者主要是介导组织的程序 在后者参与计划的同时，模式和细胞确定 细胞成熟。关于这些沉默和激活如何获得的见解 ECR/USP复合物的功能与其中的发展计划有关 昆虫模型也将直接适用于理解同源 脊椎动物中的信号系统 - 介导甲状腺作用的信号系统 激素和类视网膜类似。 具体目的是：1）确定受体和信号分子 导致果蝇的术前变化。 2）使用马赛克分析 确定ECR的配体结合和DNA结合域在中的作用 调解两个发展响应计划。 3）使用马赛克 ECR突变体的分析和ECR同工型的Misexpression检查 每个同工型支持图案和确定过程的能力 相对于成熟过程。 4）使用USP克隆和体外挑战 ecdysteroids检查细胞确定和细胞成熟程序如何 在开发过程中相互作用。 5）利用神经元蛋白细胞共培养系统 检查神经元如何指导在中表达的ECR同工型的类型 胚胎肌肉以及受体同工型选择与肌肉生长的关系 成熟反应。