myelin-basic-protein and staurosporine-aglycone

Although brain-derived neurotrophic factor (BDNF) has been shown to promote peripheral myelination during development and remyelination after injury, the precise mechanisms mediating this effect remain unknown. Here, we determine that BDNF promotes myelination of nerve growth factor-dependent neurons, an effect dependent on neuronal expression of the p75 neurotrophin receptor, whereas BDNF inhibits myelination of BDNF-dependent neurons via the full-length TrkB receptor. Thus, BDNF exerts contrasting effects on Schwann cell myelination, depending on the complement of BDNF receptors that are expressed by different subpopulations of dorsal root ganglion neurons. These results demonstrate that BDNF exerts contrasting modulatory roles in peripheral nervous system myelination, and that its mechanism of action is acutely regulated and specifically targeted to neurons.

Topics: Animals; Animals, Genetically Modified; Animals, Newborn; Brain-Derived Neurotrophic Factor; Carbazoles; Cells, Cultured; Coculture Techniques; Enzyme Inhibitors; Ganglia, Spinal; Gene Expression Regulation; Humans; Indole Alkaloids; Mice; Myelin Basic Protein; Myelin P0 Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Nerve Growth Factor; Nerve Tissue Proteins; Neurons; Rats; Rats, Sprague-Dawley; Receptors, Growth Factor; Receptors, Nerve Growth Factor; Schwann Cells; Tissue Culture Techniques; Transfection

Previous studies indicate that brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) increase myelin basic protein, (MBP) in differentiating basal forebrain (BF) oligodendrocytes (OLGs) (Du, Y., Fischer, T.Z., Lee, L.N., Lercher, L.D., Dreyfus, C. F., 2003. Regionally specific effects of BDNF on oligodendrocytes. Dev. Neurosci. 25, 116-126). While receptors, trk and p75, are expressed by subsets of oligodendrocytes (Du, Y., Fischer, T.Z., Lee, L.N., Lercher, L.D., Dreyfus, C. F., 2003. Regionally specific effects of BDNF on oligodendrocytes. Dev. Neurosci. 25, 116-126), those responsible for affecting differentiation have not been defined. In contrast, studies of peripheral Schwann cells reported that myelination is enhanced by BDNF working through p75, and diminished by trkC mediated processes (Cosgaya, J.M., Chan, J.R., Shooter, E.M., 2002. The neurotrophin receptor p75NTR as a positive modulator of myelination. Science 298, 1245-1248). To define receptors affecting central oligodendrocyte MBP, p75 knockout animals, p75 blocking antibodies, and an inhibitor of neurotrophin binding to p75, PD90780, were utilized. While p75 was implicated in the actions of NGF and NT-3, it did not affect actions of BDNF. On the other hand, K252a, an inhibitor of trk receptors, abolished the effects of the neurotrophins, including BDNF. All neurotrophins activated their respective trk receptors.

Topics: Animals; Brain-Derived Neurotrophic Factor; Carbazoles; Enzyme Inhibitors; Female; Indole Alkaloids; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Basic Protein; Nerve Growth Factor; Neurotrophin 3; Oligodendroglia; Pregnancy; Prosencephalon; Quinazolines; Rats; Rats, Sprague-Dawley; Receptor, Nerve Growth Factor; Receptor, trkA

Traditionally, the primary function of oligodendrocytes (OLGs) in the CNS has been considered to be myelination. Here, we investigated whether OLGs may play a trophic role, particularly during development. Neurotrophin expression was assessed in postnatal day 7 basal forebrain (BF) OLGs, using in situ hybridization and detection of myelin basic protein. Nerve growth factor, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) mRNAs were revealed in OLGs in vivo and in culture. To determine whether OLGs support nearby neurons, we examined the influence of OLGs on BF cholinergic neurons. Neuronal function was enhanced by cocultured OLGs and OLG conditioned medium. Moreover, trophic effects of OLG conditioned medium were partially blocked by K252a, a trk tyrosine kinase inhibitor, and by neutralizing anti-BDNF or anti-NT-3 antisera, indicating that neurotrophins may mediate these effects, perhaps in concert with other signals. Our studies support a novel role for OLGs in providing local trophic support for neurons in the CNS.

Topics: Animals; Astrocytes; Brain-Derived Neurotrophic Factor; Carbazoles; Cell Division; Cell Lineage; Cells, Cultured; Cholinergic Fibers; Coculture Techniques; Culture Media, Conditioned; Enzyme Inhibitors; Immune Sera; Indole Alkaloids; Microglia; Myelin Basic Protein; Nerve Growth Factor; Neurons; Neurotrophin 3; Oligodendroglia; Prosencephalon; Rats; Rats, Sprague-Dawley; RNA, Messenger