The extracellular factors that are responsible for inducing myelination in the central nervous system (CNS) remain elusive. We investigated whether brain-derived neurotrophic factor (BDNF) is implicated, by first confirming that BDNF heterozygous mice exhibit delayed CNS myelination during early postnatal development. We next established that the influence of BDNF upon myelination was direct, by acting on oligodendrocytes, using co-cultures of dorsal root ganglia neurons and oligodendrocyte precursor cells. Importantly, we found that BDNF retains its capacity to enhance myelination of neurons or by oligodendrocytes derived from p75NTR knockout mice, indicating the expression of p75NTR is not necessary for BDNF-induced myelination. Conversely, we observed that phosphorylation of TrkB correlated with myelination, and that inhibiting TrkB signalling also inhibited the promyelinating effect of BDNF, suggesting that BDNF enhances CNS myelination via activating oligodendroglial TrkB-FL receptors. Together, our data reveal a previously unknown role for BDNF in potentiating the normal development of CNS myelination, via signalling within oligodendrocytes.

The neurotrophin brain-derived neurotrophic factor (BDNF) has been implicated in regulating CNS myelination. BDNF mutant mice exhibit a hypomyelinating phenotype, and BDNF exerts distinct effects upon oligodendroglial proliferation, differentiation, and myelination in vitro. To investigate the precise influence that BDNF exerts in regulating CNS myelination in vivo, we have generated conditional knock-out mice in which TrkB has been deleted specifically in oligodendrocytes. Deletion of TrkB disrupted normal oligodendrocyte myelination, resulting in a significant reduction in myelin protein expression and myelination of CNS white matter tracts during development. Importantly, conditional knock-out mice exhibited normal numbers of mature oligodendrocytes and normal numbers of myelinated axons; however, myelin thickness was significantly reduced during development. These data indicate that while TrkB expression in oligodendrocytes plays no role in the initial contact with axons, it exerts an important influence in subsequent stages to promote myelin ensheathment. The conditional knock-out mice also exhibited an increased density of oligodendrocyte progenitor cells (OPCs) in CNS white matter tracts. Concordant with these results, in vitro analyses using OPCs subjected to TrkB knockdown also revealed increased OPC proliferation. Our data suggested this effect was dependent upon TrkC and p75 expression. Thus, our data demonstrate that TrkB expression in oligodendroglia exerts a direct effect on oligodendrocytes to promote myelination and an indirect effect upon the OPC population, modifying their proliferative potential.

Myelination of the vertebrate nervous system has evolved to insulate axons and to promote rapid propagation of action potentials via saltatory conduction. During development of the CNS, committed oligodendrocyte progenitor cells (OPCs) arise from stereotyped germinal regions of the CNS, proliferate, and migrate throughout the CNS before differentiating into postmitotic premyelinating oligodendrocytes (Barres and Raff 1999;Richardson et al. 2000;Baumann and Pham-Dinh 2001). These cells subsequently either ensheath axons to form myelin membrane or undergo apoptosis. However, relatively little is known about the nature of the intracellular signals that control myelination or how these are regulated. Identifying such molecules and pathways has the potential to inform novel therapeutic approaches to promote remyelination.Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors and signals through the tropomyosin-related kinase B (TrkB) receptor and the structurally unrelated p75 neurotrophin receptor (Huang and Reichardt 2001;Chao 2003). Recent studies have established that BDNF plays a key role in regulating CNS myelination, as both BDNF knockout and heterozygous Received May 17, 2012; revised manuscript received July 6, 2012; accepted July 9, 2012.Address correspondence and reprint requests to Dr Junhua Xiao, Centre for Neuroscience Research, The University of Melbourne, Victoria 3010, Australia. E-mail: xiaoj@unimelb.edu.auAbbreviations used: BDNF, brain-derived neurotrophic factor; BrdU, bromodeoxyuridine; CA, constitutively active; CNPase, 2¢,3¢-cyclic 11 nucleotide 3¢-phosphodiesterase; CREB, 2 cAMP-response element binding protein; DAPI, 4¢, 6¢-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide; DN, dominant negative; DRG, dorsal root ganglion; Erk, extracellular signal-regulated kinase; GFAP, glial fibrillary acidic protein; JNK, c-Jun N-terminal kinase; MAG, myelin associated glycoprotein; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; MEK, MAPK/Erk kinase; NGF, nerve growth factor; OPCs, oligodendrocyte progenitor cells; P, Postnatal; PDGFRa, platelet-derived growth factor receptor alpha; TrkB, tropomyosin-related kinase receptor B., , , We have previously shown that brain-derived neurotrophic factor (BDNF) promotes oligodendrocyte myelination. Here, we screened for the activation of candidate signaling pathways in in vitro myelination assays and found that extracellular signal-regulated kinase (Erk) signaling positively correlated with basal levels of oligodendrocyte myelination as well as BDNF-induced myelination in vitro. By selectively manipulating Erk1/2 activation in oligodendrocytes in vitro, we found that constitutive activation of Erk1/2 significantly increased myelination, mimicking the promyelinating effect of BDNF, and also caused myelination to occur earlier. Conversely, selective inhibition of Erk1/2 in oligodendrocytes significantly reduced the basal level of myelination and blocked the promyelinating effect of BDNF. Analysis of mye...

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.

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