CONTROL OF CNS DEVELOPMENT BY BRC TRANSCRIPTION FACTORS

BRC 转录因子对 CNS 发育的控制

• 批准号: 6266881
• 负责人: LINDA L RESTIFO
• 金额: $ 25.88万
• 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/6266881
• 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（来自申请人的摘要）：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着至关重要的作用 发育和功能。这些角色是通过正常的性行为揭示出来的 二态性，以及先天性缺陷和后天性疾病。我们是 使用果蝇（Drosophila melanogaster）作为模型系统来确定 全身激素信号转导的分子途径 中枢神经系统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 (20E) 协调 将青少年的神经系统重建为为小说服务的系统 成人的行为需要。这种重组的结果是神经和 胶质细胞生成、神经元重塑、程序性细胞死亡和全局 形态发生重排。之前的工作已经证明，广泛 20E 诱导型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，中枢视觉系统就会紊乱， 位置异常，大脑无法沿着中线融合，并且 食管下神经节（类似于脑干的区域）无法进入 头。互补的遗传、细胞和分子生物学实验是 根据 BRC 功能的工作模型，建议：(1) 个人 BRC 同工型负责中枢神经系统变态过程中的特定细胞事件； (2) BRC 蛋白通过控制靶基因的转录发挥作用， 其产品反过来介导中枢神经系统重组。为了支持这个模型， 转座子标记已识别出受 BRC-Z2 调节的基因 (H217) 和 似乎介导视觉系统组装通路的一个分支。转基因 拯救和基因镶嵌实验将揭示哪些亚型 负责中枢神经系统变态的 BRC 依赖性事件，以及何时和 需要它们的地方。大多数拟议的研究都集中在组装 中央视觉系统，包括初级细胞的测定 导致两种 BRC 视叶表型的缺陷。 H217转录 将识别单位及其基因的细胞/生化功能 研究产品以了解其在视觉组装中的作用 系统神经细胞。涉及视叶的其他候选 BRC 靶基因 将通过 BRC 依赖筛选来确定发展情况 转录增强子。一个具体的预测是，这样的突变体 目标基因将与 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 大脑发育应该导致更好的中枢神经系统治疗策略 由于先天性和后天性疾病导致的功能障碍。