Our group focuses on mechanisms of neuronal development and plasticity. Based on neurite outgrowth assays, we have previously isolated, cloned, and produced as recombinant proteins two ligands of heparan sulfate proteoglycans (HSPGs), HMGB1 (high-mobility group B1; amphoterin) and HB-GAM (heparin-binding growth-associated molecule; pleiotrophin).
In addition to heparin/heparan sulfates, HMGB1 binds to the immunoglobulin superfamily protein RAGE (receptor for advanced glycation end-products), which mediates the neurite outgrowth-promoting signal of HMGB1. AMIGO (amphoterin-induced gene and orf) has been identified as an HMGB1-induced gene in hippocampal neurons using ordered differential display. AMIGO defines a novel gene family with three closely related members (AMIGO, AMIGO 2, and AMIGO 3) that belong to both LRR (leucine-rich repeat) and Ig (immunoglobulin) superfamilies of cell surface proteins. We have recently identified AMIGO as an auxiliary subunit of the Kv2.1 potassium channel. Furthermore, AMIGO affects the channel activity and thereby excitability of neurons.
HB-GAM regulates migration of neurons in developing brain through binding to the transmembrane proteoglycan syndecan-3 (N-syndecan). In addition to HSPG binding, HB-GAM has similar carbohydrate binding sites in chondroitin sulfate proteoglycans (CSPGs). CSPGs are major inhibitory regulators of plasticity and regeneration in the CNS extracellular matrix but our recent experiments have shown that their role can be reversed from inhibition to activation by HB-GAM in the extracellular space. We are currently developing novel treatment strategies for CNS injuries based on the ability of HB-GAM and similar glycosaminoglycan-binding molecules to induce regenerative growth of neurites.