SYNAPTIC CONNECTIVITY IN CENTRAL BRAIN

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The overall goal of this proposal is to characterize the molecular mechanisms by which synapses between central interneurons are established and modulated. We will work toward that broad goal by (1) further characterizing the function of the Drosophila POU domain transcriptional regulator, Acj6, and its role in establishing correct synaptic connections in the central brain, (2) identifying other components of the pathway(s) regulated by Acj6 during synapse formation and (3) characterizing the role of the amino terminal Acj6 POUIV box in regulating Acj6 function. The specific alms of this proposal are: (1) to identify other components of the pathway(s) regulated by Acj6 through completion of a genetic screen for enhancers and suppressors of the acj6 mutant phenotype, (2) to further characterize the acj6 mutant defects in synaptic connectivity by generating Acj6 neuron-specific expression transposons for use both as cell-specific markers and for misexpression experiments, (3) to characterize the neuron-specific expression of Acj6 isoforms resulting from alternative splicing of the amino terminal POUIV box; and (4) to complete a yeast two-hybrid screen for heterologous proteins interacting with the Acj6 POUIV box. The process of synaptogenesis requires precise initial selection of the correct synaptic partners and subsequent refinement of terminal processes and connections. This process of synaptic selection, refinement, strengthening and/or elimination is thought to be important for learning and memory formation and may lie at the root of a number of neuropathologies. Genetic analysis of synaptic function in the fruit fly, Drosophila melanogaster, has contributed significantly to our knowledge of learning and memory mechanisms. In preliminary studies, we have shown that the Drosophila transcriptional regulator, Acj6, is essential for regulation of terminal axon branching and synaptogenesis in a subset of central interneurons. The significant evolutionary conservation of transcription factor interactions shown over the past several years has demonstrated the value of detailed characterization of developmental regulatory mechanisms in an organism such as Drosophila which can be more readily manipulated experimentally. Information gained from an analysis of the fundamental developmental roles played by the Acj6 protein in Drosophila can be extrapolated to higher organisms to better understand analogous processes involved in synaptic connectivity and certain developmental abnormalities.