Receptor protein tyrosine phosphatase σ binds to neurons in the adult mouse brain

•A receptor affinity probe assay shows that RPTPσ binds to neurons in sections of adult mouse brain.•RPTPσ binding does not overlap with CSPG staining in adult mouse brain cerebral cortex.•Binding of RPTPσ remains when heparan sulfate or chondroitin sulfate is removed enzymatically.•Binding of RPTPσ is displaced by incubation with CS-E and heparin but not CS-A or CS-C.•Binding of RPTPσ is altered by changes in ionic strength.

The role of type IIA receptor protein tyrosine phosphatases (RPTPs), which includes LAR, RPTPσ and RPTPδ, in the nervous system is becoming increasingly recognized. Evidence supports a significant role for these RPTPs during the development of the nervous system as well as after injury, and mutations in RPTPs are associated with human disease. However, a major open question is the nature of the ligands that interact with type IIA RPTPs in the adult brain. Candidates include several different proteins as well as the glycosaminoglycan chains of proteoglycans. In order to investigate this problem, we used a receptor affinity probe assay with RPTPσ-AP fusion proteins on sections of adult mouse brain and to cultured neurons. Our results demonstrate that the major binding sites for RPTPσ in adult mouse brain are on neurons and are not proteoglycan GAG chains, as RPTPσ binding overlaps with the neuronal marker NeuN and was not significantly altered by treatments which eliminate chondroitin sulfate, heparan sulfate, or both. We also demonstrate no overlap of binding of RPTPσ with perineuronal nets, and a unique modulation of RPTPσ binding to brain by divalent cations. Our data therefore point to neuronal proteins, rather than CSPGs, as being the ligands for RPTPσ in the adult, uninjured brain.