NgR1 and NgR3 are Receptors for Chondroitin Sulfate Proteoglycans

In the adult mammalian CNS, chondroitin sulfate proteoglycans (CSPGs) and myelin–associated inhibitors (MAIs) stabilize neuronal structure and restrict compensatory sprouting following injury. The Nogo receptor family members NgR1 and NgR2 bind to MAIs and have been implicated in neuronal inhibition. Here we show that NgR1 and NgR3 bind with high–affinity to the glycosaminoglycan moiety of proteoglycans and participate in CSPG inhibition in cultured neurons. Nogo receptor triple mutants (NgR123(−/−)), but not single mutants, show enhanced axonal regeneration following retro–orbital optic nerve crush injury. The combined loss of NgR1 and NgR3 (NgR13(−/−)), but not NgR1 and NgR2 (NgR12(−/−)), is sufficient to mimic the NgR123(−/−) regeneration phenotype. Regeneration in NgR13(−/−) mice is further enhanced by simultaneous ablation of RPTPσ, a known CSPG receptor. Collectively, these results identify NgR1 and NgR3 as novel CSPG receptors, demonstrate functional redundancy among CSPG receptors, and provide unexpected evidence for shared mechanisms of MAI and CSPG inhibition.