Two mitogenic regions of myelin basic protein interact with different receptors to induce Schwann cell proliferation in a cAMP dependent process

Abstract

Previous studies have shown that myelin basic protein (MBP) is mitogenic for Schwann cells (SCs) in the presence of elevated intracellular cAMP. Two mitogenic regions of MBP have been identified: one mitogenic region within the first 44 residues of the aminoterminus (1-44) and the other mitogenic region within the terminal 15 residues of the carboxyl end of the molecule (152-167). Unlike the mitogenic effect of a myelin enriched fraction (MEF), the mitogenic effect of MBP was not reduced by the addition of the lysosomal inhibitor, ammonium chloride. These data indicate that MBP causes SC proliferation by direct interaction of MBP with a surface receptor. Using Scatchard analysis of the binding of MBP to SCs, we report that treatment with forskolin does not cause the upregulation of receptors for MBP. Moreover, MBP blocks the cross-linking of 125I-bFGF with two fibroblast growth factor (FGF) receptors having apparent molecular weights of 140 kDa and 120 kDa, respectively. Since neither TGF-beta nor PDGF-BB displaced cell surface bound 125I-MBP, we conclude that MBP binds to the FGF receptor rather than other growth factor receptors. Furthermore, only MBP interacted with ganglioside GM1, whereas MBP did not interact with this ganglioside. These results are consistent with the view that ganglioside GM1 mediates the mitogenic effects of MBP, while the FGF receptor mediates the mitogenic effect of MBP. Intracellular cAMP of SCs was transiently increased after the addition of macrophage conditioned medium, suggesting that macrophages may produce factors in vivo which can transiently elevate intracellular cAMP levels, allowing a wave of SC proliferation in response to MBP-related mitogens.

Cultured neonatal schwann cells contain and secrete neuregulins

“…Recent evidence suggests that the re-establishment of axonal contact after nerve injury does not elicit SC mitosis (Siironen et al, 1994). Our laboratory has implicated a myelin basic protein as a potential mitogen for SC after neural injury (Baichwal and DeVries, 1992;Tzeng et al, 1995). Since the molecule(s) responsible for initiating mitosis following neural injury are not known, our present results raise the possibility that SC-derived NDF may also contribute to the mitogenic response observed in SC following neural injury.…”

Influence of IN-1 antibody and acidic FGF-fibrin glue on the response of injured corticospinal tract axons to human Schwann cell grafts

“…It is also possible that aFGF influences the interaction between injured, sprouting CST fibers and the grafted SCs. Basic FGF may be capable of inducing SC mitogenesis in the presence of other supportive molecules (Peulve et al, 1994;Tzeng et al, 1995;B.T. Zhang et al, 1995).…”

Exogenous myelin basic protein promotes oligodendrocyte death via increased calcium influx

“…lD, arrow). As shown in Figure 2, MBP induced the death of OLGs in a dosedependent manner at the concentrations of MBP previously shown to stimulate SC proliferation (Tzeng et al, 1995;submitted). Since the isoelectric points of MBP and cytochrome-C are similar, cytochrome-C was used to examine whether or not the highly charged nature of MBP is responsible for OLG death.…”

“…Two mitogenic regions have been identified in MBP; one mitogenic region is located on the initial 44 residues of the amino-terminus (the 1-44 region), and the other mitogenic region is located on the last 15 residues of the carboxyl terminus (the 152-167 region) (Tzeng et al, submitted). Furthermore, our data suggest that the 1-44 region of MBP interacts with ganglioside GM1 to stimulate SC proliferation, while the 152-167 region of MBP interacts with the FGF receptor to cause SC proliferation (Tzeng et al, 1995;submitted).…”