Neuron-glia interaction - novel neural trophic factors and their molecular action mechanism -

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Two kinds of novel neural trophic factors were detected in von Recklinghausen neurofibroma (NF1) extracts. one of two, neuroblastoma growth factor (Mr<5 kDa), promotes the proliferation of human neuroblastoma cell and survival and neurite-extension of rat cortical neuron, but is distinct from nerve growth factor (NGF) or NGF-like factors. The other trophic factor is a glial growth inhibitor (Mr=100 k), which suppresses the growth of glioma cell lines, astrocytoma, glioblastoma, oligodendroglioma and Schwannoma. These factors do not appear to be previously identified cytokines or growth factors such as interleukins, granulocyte colony-stimu-lating factor, NGF and fibroblast growth factor, Ciliary neurotrophic factor-like activity was also detected in the extracts. Anovel endogenous polypeptide inhibitor of proliferation and DNA synthesis of glial cells, gliostatin, was purified from the extracts of neurofibroma by a procedure comprising column chromatography with Blue-Toyopearl and DEAE-Sephacel, and high-performance liquid chromatography with Butyl-Toyopearl, Hydroxylapatite and Mono Q. monoclonal antibody raised against partially purified (Hydroxylapatite step) gliostatin adsorbed the growth inhibitory activity of gliostatin and immunochemically visualized the putative gliostatin bands on Western blot analyses, but showed no cross-reactivity with known cytokinesis. Although the product showed an apparent Mr=100 k accompanied by an inhibitory activity on Superdex 200 column chromatography, it migrated at a lower apparent Mr=50 k under the reducing condition on Western blotting, indicating that a homodimeric structure of native gliostatin consisted of 50 KDa subcomponents. Gliostatin was a potent growth inhibitor acting at nM concentration against all glial tumor cells d glia maturation factor (GMF)-stimulated astroblasts but not neuronal cells.