Regulation of Drosophila Brain Wiring by Neuropil Interactions via a Slit-Robo-RPTP Signaling Complex

The axonal wiring molecule Slit and its Round-About (Robo) receptors are conserved regulators of nerve cord patterning. Robo receptors also contribute to wiring brain circuits. Whether molecular mechanisms regulating these signals are modified to fit more complex brain wiring processes is unclear. We investigated the role of Slit and Robo receptors in wiring Drosophila higher-order brain circuits and identified differences in the cellular and molecular mechanisms of Robo/Slit function. First, we find that signaling by Robo receptors in the brain is regulated by the Receptor Protein Tyrosine Phosphatase RPTP69d. RPTP69d increases membrane availability of Robo3 without affecting its phosphorylation state. Second, we detect no midline localization of Slit during brain development. Instead, Slit is enriched in the mushroom body, a neuronal structure covering large areas of the brain. Thus, a divergent molecular mechanism regulates neuronal circuit wiring in the Drosophila brain, partly in response to signals from the mushroom body.VIB WiBrain Interuniversity Attraction Pole (BELSPO IUAP) network Fonds Wetenschappelijke Onderzoek (FWO) G.0543.08 G.0680.10 G.0681.10 G.0503.12 FONDECYT 11150610 Wellcome Trust 087742/Z/08/Z Biotechnology and Biological Sciences Research Council BB/M007456/1 BB/I002448/1 Universities of Liverpool and Manchester Becas Chile University of Leuven FWO ICM-P09015