Leukocyte-common antigen related (LAR)-like phosphatase receptors are conserved cell adhesion molecules that function in multiple developmental processes. The Caenorhabditis elegans
ptp-3 gene encodes two LAR family isoforms that differ in the extracellular domain. We show here that the long isoform, PTP-3A, localizes specifically at synapses and that the short isoform, PTP-3B, is extrasynaptic. Mutations in
ptp-3 cause defects in axon guidance that can be rescued by PTP-3B but not by PTP-3A. Mutations that specifically affect
ptp-3A do not affect axon guidance but instead cause alterations in synapse morphology. Genetic double-mutant analysis is consistent with
ptp-3A acting with the extracellular matrix component nidogen,
nid-1, and the intracellular adaptor alpha-liprin,
syd-2.
nid-1 and
syd-2 are required for the recruitment and stability of PTP-3A at synapses, and mutations in
ptp-3 or
nid-1 result in aberrant localization of SYD-2. Overexpression of PTP-3A is able to bypass the requirement for
nid-1 for the localization of SYD-2 and RIM. We propose that PTP-3A acts as a molecular link between the extracellular matrix and alpha-liprin during synaptogenesis.