Elucidating Slit-Independent Mechanisms of Robo Receptors Regulating Neural Circuit Formation and Head Morphogenesis in C. elegan

Robo receptor is a central component in multiple stages of neural development. Accumulating evidence also suggests that it functions in organogenesis, regulation of stem cells, and cancer. Despite its diverse functions, all of the reported functions of Robo rely on binding with its canonical ligand, Slit. However, it has long been known that in C. elegans, which has only one Slit (slt-1) and one Robo (sax-3) gene, mutants of Robo exhibit more severe phenotypes than Slit mutants, suggesting that Robo has Slit-independent functions. This proposal aims to explain some of the Slit-independent Robo mutantphenotypes: 1) defects in formation of the RME circuit, a head motor neural circuit, and 2) notched head in C. elegans. Preliminary results suggest that SAX-3 acts as its own ligand in mediating RME circuit formation. More surprisingly, the extracellular domain of SAX-3 can rescue the notched head phenotype. The proposed work is an essential step towards comprehensive understanding of Robo receptors and may provide insights in understanding

human genetic diseases.