CONTROL OF CNS DEVELOPMENT BY BRC TRANSCRIPTION FACTORS

BRC 转录因子对 CNS 发育的控制

• 批准号: 6637045
• 负责人: LINDA L RESTIFO
• 金额: $ 23.86万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-09 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637045
• 关键词: Drosophilidae; biological models; cell differentiation; cellular pathology; central nervous system; congenital vision disorder; developmental neurobiology; ecdysone; gene expression; genetic mapping; hormone regulation /control mechanism; immunocytochemistry; invertebrate endocrinology; metamorphosis; molecular cloning; molecular genetics; morphometry; mutant; neural plasticity; neuroanatomy; neurogenesis; protein isoforms; protein structure function; transcription factor; visual pathways

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.

描述（摘自申请人的摘要）：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关键作用 发展和功能。这些角色通过正常性揭示 二态性以及先天性缺陷和获得的疾病。我们是 使用果蝇果蝇Melanogaster作为模型系统来确定 将全身激素信号转导到的分子途径 CNS发育过程中的特定细胞和形态发生变化。期间 昆虫的塑性类固醇激素20-羟基丁香（20E）编排 少年神经系统重建为小说的神经系统 成人的行为需求。这种重组是由神经和 神经胶质发生，神经元重塑，程序性细胞死亡和全局 形态发生重排。以前的工作表明了广泛的 复合物（BRC）20E诱导，锌指转录因子的家族 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，中央视觉系统会混乱，并且 异常位置，大脑无法沿中线融合， 食道下神经节（类似于脑干的区域）未能进入 头。互补的遗传，细胞和分子生物学实验是 提出的，基于BRC功能的工作模型：（1）单个BRC 同工型在中枢神经系统变形过程中负责特定的细胞事件。 （2）BRC蛋白通过控制靶基因的转录来起作用， 其产品又介导了CNS的重组。为了支持这个模型， 转座子标记已确定一个由BRC-Z2和的基因（H217） 似乎可以介导视觉系统组装途径的一个分支。转基因 救援和遗传镶嵌实验将揭示哪些同工型是 负责CNS变形的BRC依赖性事件，以及何时及 需要的地方。大多数拟议的研究都集中在集会上 中央视觉系统，包括确定主要细胞 引起两个BRC光叶表型的缺陷。 H217转录 将识别单位和其基因的细胞/生化功能 为了了解其在视觉组装中的作用而进行了研究 系统神经膜。其他候选BRC靶基因涉及光叶 将通过依赖BRC的屏幕来确定开发 转录增强剂。一个具体的预测是这样的突变体 靶基因将与BRC突变体共享视觉系统缺陷，H217也是如此。 定义激素信号和特定事件之间的分子途径 大脑发育应带来更好的治疗策略来治疗中枢神经系统 由于先天性和后疾病引起的功能障碍。