Three Drosophila Liprins Interact to Control Synapse Formation

Liprin-alpha proteins are adaptors that interact with the receptor protein tyrosine phosphatase leukocyte common antigen-related (LAR) and other synaptic proteins to promote synaptic partner selection and active zone assembly. Liprin-beta proteins bind to and share homology with Liprin-alpha proteins, but their functions at the synapse are unknown. The Drosophila genome encodes single Liprin-alpha and Liprin-beta homologs, as well as a third related protein that we named Liprin-gamma. We show that both Liprin-beta and Liprin-gamma physically interact with Liprin-alpha and that Liprin-gamma also binds to LAR. Liprin-alpha mutations have been shown to disrupt synaptic target layer selection by R7 photoreceptors and to reduce the size of larval neuromuscular synapses. We have generated null mutations in Liprin-beta and Liprin-gamma to investigate their role in these processes. We find that, although Liprin-beta mutant R7 axons terminate before reaching the correct target layer, Liprin-beta mutant R7 axons grow beyond their target layer. Larval neuromuscular junction size is reduced in both Liprin-alpha and Liprin-beta mutants, and further reduced in double mutants, suggesting independent functions for these Liprins. Genetic interactions demonstrate that both Liprin proteins act through the exchange factor Trio to promote stable target selection by R7 photoreceptor axons and growth of neuromuscular synapses. Photoreceptor and neuromuscular synapses develop normally in Liprin-gamma mutants; however, removing Liprin-gamma improves R7 targeting in Liprin-alpha mutants, and restores normal neuromuscular junction size to Liprin-beta mutants, suggesting that Liprin-gamma counteracts the functions of the other two Liprins. We propose that context-dependent interactions between the three Liprins modulate their functions in synapse formation.