Leukocyte Common Antigen-Related Phosphatase Is a Functional Receptor for Chondroitin Sulfate Proteoglycan Axon Growth Inhibitors

Abstract

CSPGs (chondroitin sulfate proteoglycans) are a family of extracellular matrix molecules with various functions in regulating tissue morphogenesis, cell division and axon guidance. A number of CSPGs are highly upregulated by reactive glial scar tissues after injuries and form a strong barrier for axonal regeneration in the adult vertebrate CNS. Although CSPGs may negatively regulate axonal growth via binding and altering activity of other growth-regulating factors, the molecular mechanisms by which CSPGs restrict axonal elongation are not well understood. Here, we identified a novel receptor mechanism whereby CSPGs inhibit axonal growth via interactions with neuronal transmembrane LAR (the leukocyte common antigen-related phosphatase). CSPGs bind LAR with high affinity in transfected COS-7 cells and co-immunoprecipitate with LAR expressed in various tissues including the brain and spinal cord. CSPG stimulation enhances activity of LAR phosphatase in vitro. Deletion of LAR in knockout mice or blockade of LAR with sequence-selective peptides significantly overcomes neurite growth restrictions of CSPGs in neuronal cultures. Intracellularly, CSPG-LAR interaction mediates axonal growth inhibition of neurons partially via inactivating Akt and activating RhoA signals. Systemic treatments with LAR-targeting peptides in mice with thoracic spinal cord transection injuries induce significant axon growth of descending serotonergic fibers in the vicinity of the lesion and beyond in the caudal spinal cord and promote locomotor functional recovery. Identification of LAR as a novel CSPG functional receptor provides a therapeutic basis for enhancing axonal regeneration and functional recovery after CNS injuries in adult mammals.

A sulfated carbohydrate epitope inhibits axon regeneration after injury

“…Interestingly, residual inhibition by CS-E (approximately 22%) remained in PTPσ-deficient neurons, consistent with previous observations with CSPGs (22). These results suggest that CS-E may also engage other receptors, possibly leukocyte common antigen-related phosphatase (LAR) (27) and as-yet-undiscovered receptors, although we cannot rule out additional receptor-independent mechanisms, such as charge repulsion or reduced cell adhesion. Together, these studies demonstrate that the fine structure of CS chains mediates interactions with receptors involved in axon regeneration, and they identify PTPσ as a critical functional receptor for CS-E.…”

Semaphorin 3A Binds to the Perineuronal Nets via Chondroitin Sulfate Type E Motifs in Rodent Brains

“…The possible additive effect of Sema3A with PNN-GAGs could be attributed by the independent signaling pathways these two families of molecules are eliciting. Whereas Sema3A signals through the neuropilin-1 (NP-1)/plexin receptor complex (47)(48)(49)(50), the inhibition from CSs in the PNN-GAGs can be triggered via the recently identified receptors, such as protein-tyrosine phosphatase-, leukocyte common-related phosphatase, Nogo receptors, or contactin pathways (51)(52)(53)(54). It is possible that the simultaneous presentation of both Sema3A and CSs on the neuronal surface confer stronger inhibitory properties to the PNNs, which will trigger both inhibitory signaling pathways in the incoming growth cones and therefore exclude new connections from PNN-surrounded neurons in the adult CNS.…”

“…Recent reports have implicated the role of PNNs in the modulation of synapses through AMPA receptor mobility, which is unlikely to involve Sema3A (56,57). Moreover, several CSPG receptors, such as protein-tyrosine phosphatase-, contactin, and Nogo receptor 3, are also widely expressed in the CNS (51)(52)(53)(54). They may mediate growth inhibition by directly binding to the CS GAGs (27).…”

Remyelination Therapy for Multiple Sclerosis

“…Apart from enzymatic degradation through proteases or chondroitinase ABC, interfering with enzymes involved in CSPG biosynthesis, such as chondroitin polymerizing factor or xylotransferase-1, have been effective in promoting axon growth in the presence of CSPGs [131,132]. Alternatively, the receptors that bind CSPGs, including protein tyrosine phosphatase-σ, leukocyte common antigen-related phosphatase, or Nogo-66 receptor 1 and 3, could potentially be targets for the development of antagonistic inhibitors [133][134][135]. It is important to note that the majority of work investigating CSPG-mediated inhibition has been focused on growth of neurites after traumatic injuries, and inhibition of OPCs by CSPGs has only recently been put in the spotlight [126,127,130].…”