CONTROL OF CNS DEVELOPMENT BY BRC TRANSCRIPTION FACTORS

描述(摘自申请者的摘要)：通过调节基因模式 表达、类固醇和甲状腺激素在神经系统中起着关键作用 发展和功能。这些角色是通过正常的性行为表现出来的 二相性，以及先天缺陷和后天疾病。我们是 以果蝇--黑腹果蝇为模型系统 全身性激素信号转导的分子途径 中枢神经系统发育过程中特殊的细胞和形态发生变化。在.期间 类固醇激素20-羟基蜕皮酮(20E)对昆虫变态的调控 将青少年的神经系统重建成为小说服务的神经系统 成年人的行为需求。这种重组是由神经和 胶质形成、神经元重塑、程序性细胞死亡和全局性 形态发生重排。之前的工作已经证明， 20E诱导的锌指转录因子复合体(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，中央视觉系统就会紊乱， 位置不正常，大脑不能沿着中线融合， 食道下神经节(与脑干相似的区域)不能进入 头部。互补的遗传、细胞和分子生物学实验是 基于BRC功能的工作模型，提出：(1)个体BRC 异构体负责中枢神经系统变态过程中的特定细胞事件； 以及(2)BRC蛋白通过控制靶基因的转录而起作用， 其产品反过来又介导了中枢神经系统的重组。为了支持这一模式， 转座子标签发现了一个受BRC-Z2和BRC-Z2调控的基因(H217)。 似乎参与了视觉系统组装途径的一个分支。转基因 拯救和基因镶嵌实验将揭示哪些亚型是 负责中枢神经系统变态的BRC依赖事件，以及何时和 在需要它们的地方。大多数拟议的研究都集中在组装 中枢视觉系统，包括初级细胞的测定 导致两种BRC视叶表型的缺陷(S)。H_217转录 单位将被鉴定及其基因的细胞/生化功能 调查产品以了解其在视觉装配中的作用 系统神经枕头。与视叶相关的其他候选BRC靶基因 开发将通过BRC依赖的屏幕进行标识 转录增强剂。一个具体的预测是，这样的突变 靶基因将与brc突变体共享视觉系统缺陷，h217也是如此。 确定荷尔蒙信号和特定事件之间的分子通路 大脑发育应该导致更好的治疗中枢神经系统的策略 先天性和获得性疾病引起的功能障碍。

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.