Precise communication between the immunoglobulin superfamily proteins NEPHRIN and NEPH1 is a prerequisite for the assembly of functional neuronal circuits and formation of the kidney filtration barrier. Mutations in NEPHRIN cause congenital nephrotic syndrome. The C. elegans homologs of NEPHRIN and NEPH1, SYG-2 and SYG-1, are critical regulators of synapse development. A major goal of this proposal is to decode the molecular processes that link the NEPH-NEPHRIN cell-cell adhesion module to intracellular signaling pathways and the actin cytoskeleton in vivo, using C. elegans synapse formation as model system. We have established a C. elegans system to study NEPHRIN and NEPH intra- and extracellular networks that are required for synaptogenesis. Using the C. elegans system, the function of slit diaphragm (SD) components as well as novel SD-associated candidates will be investigated in the functional context of synaptogenesis and axon branch formation. Furthermore, this model system provides a unique opportunity to screen for regulators of the F-actin network in vivo. Due to the exceptionally high conservation of NEPHRIN and NEPH proteins during evolution, this project will represent a unique opportunity to elucidate the fundamental mechanisms shared between synaptogenesis and podocyte functions.