Abstract
Chondroitin sulfate (CS) glycosaminoglycans inhibit regeneration in the adult central nervous system (CNS). We report here that HB-GAM (heparin-binding growth-associated molecule; also known as pleiotrophin), a CS-binding protein expressed at high levels in the developing CNS, reverses the role of the CS chains in neurite growth of CNS neurons in vitro from inhibition to activation. The CS-bound HB-GAM promotes neurite growth through binding to the cell surface proteoglycan glypican-2; furthermore, HB-GAM abrogates the CS ligand binding to the inhibitory receptor PTPσ (protein tyrosine phosphatase sigma). Our in vivo studies using two-photon imaging of CNS injuries support the in vitro studies and show that HB-GAM increases dendrite regeneration in the adult cerebral cortex and axonal regeneration in the adult spinal cord. Our findings may enable the development of novel therapies for CNS injuries.
Highlights
HB-GAM/pleiotrophin was initially isolated as a heparin-binding neurite outgrowth-promoting factor for central neurons[8,9]
Inhibition of neurite outgrowth by aggrecan and the reversing effect by HB-GAM were observed in the same manner as in assays where aggrecan was coated on the culture wells (Supplementary Fig. S2b)
We found that HB-GAM displayed binding to CS but not to PTPσin a solid phase binding assay showing that HB-GAM binds to aggrecan and not to PTPσ(Supplementary Fig. S4f), and PTPσwas not found as an HB-GAM-binding component in bead assays using CNS neurons (Table 1)
Summary
HB-GAM/pleiotrophin was initially isolated as a heparin-binding neurite outgrowth-promoting factor for central neurons[8,9]. Its expression peaks during the first 3–4 weeks of postnatal development in rat brain[10] corresponding to heightened plasticity of the juvenile brain[11]. The growth factor Midkine, which displays homology with HB-GAM, was recently reported to partially overcome CSPG inhibition of neurite extension[16]. Taken together, these studies suggest HB-GAM as a candidate molecule to modify interactions of CNS neurons with inhibitory ECM structures such as CSPGs. the possibility that HB-GAM could overcome or even reverse the inhibitory effects of the ECM on growth and regeneration of neurites has not previously been explored
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