CONTROL OF CNS DEVELOPMENT BY BRC TRANSCRIPTION FACTORS

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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.