CONTROL OF CNS DEVELOPMENT BY BRC TRANSCRIPTION FACTORS

描述（来自申请人的摘要）：通过调节基因的模式， 类固醇和甲状腺激素在神经系统中起着重要作用 发展和功能。这些角色通过正常的性行为来揭示 二型，以及先天性缺陷和后天性疾病。我们 使用果蝇，果蝇，作为模型系统，以确定 系统性激素信号被转导到 CNS发育过程中特定的细胞和形态发生变化。期间 昆虫变态由类固醇激素20-羟基蜕皮激素（20 E）协调 将少年神经系统重建为小说服务 成年人的行为需求。这种重组是由神经和 神经胶质细胞生成、神经元重塑、程序性细胞死亡和整体 形态发生重排以前的研究表明， 20 E-诱导型锌指转录因子复合物（BRC）家族 控制中枢神经系统形态发生和视觉系统组装的特定特征。 当BRC功能受损时，中央视觉系统紊乱， 位置异常，大脑不能沿中线沿着融合， 食管下神经节（一个类似于脑干的区域）无法进入 头部补充遗传，细胞和分子生物学实验 建议，基于一个工作模式的BRC功能：（1）个人BRC 同种型负责CNS变态期间的特定细胞事件; 和（2）BRC蛋白通过控制靶基因的转录起作用， 其产物反过来介导CNS重组。为了支持这一模式， 转座子标记已经鉴定了由BRC-Z2调节的基因（H217）， 似乎介导视觉系统组装途径的一个分支。转基因 拯救和遗传嵌合体实验将揭示哪些同种型是 负责CNS变态的BRC依赖性事件，以及 在需要的地方。大多数拟议的研究集中在组装的 中央视觉系统，包括确定主要的细胞 导致两种BRC视叶表型的缺陷。H217转录 将识别出该单位，并确定其基因的细胞/生化功能 产品调查，以了解其在视觉装配中的作用， 系统神经柱。参与视叶的其他候选BRC靶基因 将通过筛查BRC依赖性 转录增强子。一个具体的预测是，这样一个突变体， 靶基因将与BRC突变体共享视觉系统缺陷，如H217。 确定激素信号和特定事件之间的分子途径， 大脑发育应导致更好的治疗策略，用于治疗中枢神经系统 由于先天性和后天性疾病造成的机能障碍。

DESCRIPTION (From the Applicant's Abstract): By regulating patterns of gene expression, steroid and thyroid hormones play critical roles in nervous system development and function. These roles are revealed by normal sexual dimorphisms, as well as by congenital defects and acquired diseases. We are using the fruit fly, Drosophila melanogaster, as a model system to determine the molecular pathways by which a systemic hormone signal is transduced into specific cellular and morphogenetic changes during CNS development. During insect metamorphosis the steroid hormone 20-hydroxyecdysone (20E) orchestrates the reconstruction of a juvenile nervous system into one that serve the novel behavioral needs of the adult. This reorganization results from neuro- and gliogenesis, neuronal remodeling, programmed cell death, and global morphogenetic rearrangements. Previous work has demonstrated that the Broad Complex (BRC) family of 20E-inducible, zinc-finger transcription factors controls specific features of CNS morphogenesis and visual system assembly. When BRC functions are impaired, the central visual system is disorganized and abnormally positioned, the brain fails to fuse along the midline, and the subesophageal ganglion (a region similar to the brainstem) fails to move into the head. Complementary genetic, cell and molecular biological experiments are proposed, based on a working model of BRC function: (1) that individual BRC isoforms are responsible for specific cellular events during CNS metamorphosis; and (2) that BRC proteins act by controlling transcription of target genes, whose products in turn mediate CNS reorganization. In support of this model, transposon tagging has identified a gene (H217) that is regulated by BRC-Z2 and appears to mediate one branch of the visual system assembly pathway. Transgenic rescue and genetic mosaic experiments will reveal which isoforms are responsible for the BRC-dependent events of CNS metamorphosis, and when and where they are required. Most of the proposed studies focus on assembly of the central visual system, including determination of the primary cellular defects(s) that cause the two BRC optic lobe phenotypes. The H217 transcription unit will be identified and the cellular/biochemical function of its gene product investigated in order to understand its role in assembly of visual system neuropils. Additional candidate BRC target genes involved in optic lobe development will be identified through a screen for BRC-dependent transcriptional enhancers. A specific prediction is that mutants of such a target gene will share visual system defects with BRC mutants, as does H217. Defining molecular pathways between hormonal signals and specific events in brain development should lead to better therapeutic strategies for treating CNS dysfunction due to congenital and acquired disorders.