Glia
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Vestibular schwannomas (VSs) are benign tumors that arise from the Schwann cells (SCs) lining the vestibular nerve. VS cells survive and proliferate far from neurons and axonally derived growth factors. We have previously shown that VSs produce the glial growth factor, neuregulin-1 (NRG1), and its receptors, ErbB2 and ErbB3. ⋯ Furthermore, conditioned medium from VS cell cultures contains NRG1 and stimulates SC proliferation in SC cultures, an effect that is inhibited by anti-NRG1 and HCN. These data suggest an autocrine pathway of VS growth stimulation involving NRG and ErbB receptors. Inhibition of constitutive NRG:ErbB signaling reduces VS cell proliferation in vitro and may have therapeutic potential for patients with VSs.
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Parathyroid hormone-related peptide (PTHrP) is widely distributed in the rat nervous system, including the peripheral nervous system, where its function is unknown. PTHrP mRNA expression has recently been shown to be significantly elevated following axotomy of sympathetic ganglia, although the role of PTHrP was not investigated. The role of PTHrP in peripheral nerve injury was investigated in this study using the sciatic nerve injury model and dorsal root ganglion (DRG) explant model of nerve regeneration. ⋯ In addition to stimulating migration of Schwann cells along the axonal membrane, PTHrP also stimulates migration on a type 1 collagen matrix. Furthermore, treatment of purified Schwann cell cultures with PTHrP results in the rapid phosphorylation of the cAMP response element protein, CREB. We propose that PTHrP acts by promoting the dedifferentiation of Schwann cells, a critical requirement for successful nerve regeneration and an effect consistent with known PTHrP functions in other cellular differentiation programs.
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Complement-receptor-3 (CR3/MAC-1), scavenger-receptor-AI/II (SRAI/II), and Fcgamma-receptor (FcgammaR) can mediate myelin phagocytosis in macrophages and microglia. Paradoxically, after injury to CNS axons these receptors are expressed but myelin is not phagocytosed, suggesting that phagocytosis is subject to regulation between efficient and inefficient states. In the present work, we focus on CR3/MAC-1 and SRAI/II-mediated myelin phagocytosis. ⋯ Altogether, our observations suggest that CR3/MAC-1 and SRAI/II-mediated myelin phagocytosis share activation by PI3K, PLCgamma and cPKC. The two differ, however, in that non-PKC DAG-driven molecule(s) inhibit CR3/MAC-1-mediated phagocytosis, whereas nPKC inhibit SRAI/II-mediated phagocytosis. Each of these signaling steps may be targeted for regulating CR3/MAC-1 and/or SRAI/II-mediated phagocytosis between efficient and inefficient states.