Sticks and Stones, a conserved cell surface ligand for the Type IIa RPTP Lar, regulates neural circuit wiring in...

Type IIa receptor-like protein tyrosine phosphatases (RPTPs) are essential for neural development. They have cell adhesion molecule (CAM)-like extracellular domains that interact with cell-surface ligands and coreceptors. We identified the immunoglobulin superfamily CAM Sticks and Stones (Sns) as a new partner for the Drosophila Type IIa RPTP Lar. Lar and Sns bind to each other in embryos and in vitro, and the human Sns ortholog, Nephrin, binds to human Type IIa RPTPs. Genetic analysis shows that Lar and Sns function together to regulate larval neuromuscular junction development, axon guidance in the mushroom body (MB), and innervation of the optic lobe (OL) medulla by R7 photoreceptors. In the neuromuscular system, Lar and Sns are both required in motor neurons, and may function as coreceptors. In the MB and OL, however, the relevant Lar-Sns interactions are in trans (between neurons), so Sns functions as a Lar ligand in these systems.