The p75 receptor mediates axon growth inhibition through an association with PIR-B

Y Fujita,T Yamashita,S Endo,R Takashima,T Takai

doi:10.1038/cddis.2011.85

Abstract

The Nogo receptor and paired immunoglobulin-like receptor B (PIR-B) are receptors for three myelin-derived axon-growth inhibitors, including myelin-associated glycoprotein (MAG). In this study, we report that the p75 receptor is required for the signal transduction of PIR-B, which interacted with p75 upon ligand binding. In addition, p75 was required for activation of Src homology 2-containing protein tyrosine phosphatase (SHP), which is induced by MAG binding to PIR-B. Mice carrying a mutation in the p75 gene showed promotion of axonal regeneration after optic nerve injury. Thus, our results indicate that p75 has a critical role in axon growth inhibition in specific neuronal tracts.

Highlights

B associates with and inactivates tropomyosin-receptor kinase (Trk) neurotrophin receptors through SHP-1/2.4 this reaction is responsible for axon growth inhibition, the precise mechanism of signal transduction mediated by PIR-B remained to be determined. p75 is a receptor for neurotrophins and modulates the function of Trk receptors.[5]
We first assessed the possible involvement of p75 in the PIR-B signal transduction pathway by performing coimmunoprecipitation experiments in COS-7 cells transfected with plasmids encoding carboxy-terminal hemagglutinin (HA)tagged full-length p75 (p75 FL-HA) and/or full-length PIR-B (PIR-B FL)
To separate the PIR-B signal from the Nogo receptor (NgR) signal, we focused on the recent finding that MAG stimulation induces dephosphorylation of Trk receptors, which is required for PIR-B-mediated axon growth inhibition.[4]

Summary

Results

P75 interacts with PIR-B upon ligand binding in neurons. We first assessed the possible involvement of p75 in the PIR-B signal transduction pathway by performing coimmunoprecipitation experiments in COS-7 cells transfected with plasmids encoding carboxy-terminal hemagglutinin (HA)tagged full-length p75 (p75 FL-HA) and/or full-length PIR-B (PIR-B FL). To separate the PIR-B signal from the NgR signal, we focused on the recent finding that MAG stimulation induces dephosphorylation of Trk receptors, which is required for PIR-B-mediated axon growth inhibition.[4] We transfected PIR-B, HA-TrkB, and/or p75-Myc constructs into COS-7 cells, which, as assessed by immunoblot analysis, do not express detectable levels of endogenous PIR-B, TrkB, or p75 (data not shown). These cells were treated with MAG-Fc for 30 min, and the TrkB p75. The regeneration of optic nerve axons was traced by injecting the cholera toxin beta subunit (CTB) conjugated to Alexa Fluor 555 (Invitrogen, Carlsbad, CA, USA) into the vitreous of the retina 12 days after the

Discussion

Materials and Methods