Development and Function of Medulla Tangential Neurons - The process by which the brain is assembled into an organized structure in which cell bodies, axon tracts, and dense synaptic neuropils occupy consistent locations is not well understood. In particular, the potential role of tangentially projecting neurons in organizing brain structure merits further investigation. Transient tangential pioneers in the subplate of the developing human cortex are thought to establish a framework for long-range connections, and defects in these neurons have been implicated in the pathogenesis of neurodevelopmental disorders. Tangentially projecting neurons can more readily be studied in the Drosophila visual system, which is amenable to rapid genetic analysis. Recent advances in understanding cell fate specification, gene expression in individual cell types, and connectivity have made this a relatively well described model system in which to address developmental and functional questions. However, visual projection neurons in the largest optic lobe, the medulla, have been excluded from many of these analyses. Recent results show that Plexin A provided by these tangentially projecting neurons organizes the layered structure of the medulla neuropil, emphasizing their importance for optic lobe assembly. This exploratory proposal will focus on characterizing the development and function of medulla visual projection (MeVP) neurons. The first aim will use lineage tracing to determine which neuroblasts give rise to MeVP neurons. As MeVP neurons constitute a small subset of all medulla neurons, these cells will be partially purified to facilitate a targeted transcriptomic analysis of their gene expression profiles. The results of this analysis will in turn enable the development of further tools that can be used to study and manipulate MeVP neurons. The second aim will investigate the mechanisms that direct MeVP neurons to send dendritic projections perpendicularly to the majority of medulla neurons and axonal projections into the central brain. Transgenic RNAi will be used to deplete guidance receptors that are expressed in these neurons and the effects on their projections will be examined. In addition, targeted ablation of MeVP neurons or their processes will reveal whether they provide cues other than Plexin A to organize the medulla neuropil. If so, these cues will be identified by RNAi knockdown of candidate transmembrane or secreted proteins derived from the transcriptomic analysis in Aim 1. Integrating this class of neurons into current models of the development of the visual circuitry will provide a more complete description of the system, and will potentially shed light on the role of tangentially projecting neurons in the developing human brain.
