title: Fyn is an intermediate kinase that BDNF utilizes to promote oligodendrocyte myelination.
abstract: Fyn, a member of the Src family of nonreceptor tyrosine kinases, promotes central nervous system myelination during development; however the mechanisms mediating this effect remain unknown. Here we show that Fyn phosphorylation is modulated by BDNF in vivo. Concordant with this, we find that BDNF stimulates Fyn phosphorylation in myelinating cocultures, an effect dependent on oligodendroglial expression of TrkB. Importantly, PP2, a pharmacological inhibitor of Src family kinases, not only abrogated the promyelinating influence of BDNF in vitro, but also attenuated BDNF-induced phosphorylation of Erk1/2 in oligodendrocytes. Over-expression of Fyn in oligodendrocytes significantly promotes phosphorylation of Erk1/2, and promotes myelination to the extent that exogenous BDNF exerts no additive effect in vitro. In contrast, expression of a kinase-dead mutant of Fyn in oligodendrocytes significantly inhibited BDNF-induced activation of Erk1/2 and abrogated the promyelinating effect of BDNF. Analysis of white matter tracts in vivo revealed that phosphorylated Fyn primarily colocalized with mature oligodendrocytes, and was rarely observed in oligodendrocyte progenitor cells, a profile that closely parallels the detection of phosphorylated Erk1/2 in the developing central nervous system. Taken together, these data identify that Fyn kinase exerts a key role in mediating the promyelinating influence of BDNF. Here we identify a pathway in which BDNF activation of oligodendroglial TrkB receptors stimulates the phosphorylation of Fyn, a necessary step required to potentiate the phosphorylation of Erk1/2, which in turn regulates oligodendrocyte myelination.
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, 3010, Australia.
authors.forename: Haley
authors.initials: H
authors.lastname: Peckham
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, 3010, Australia.
authors.forename: Lauren
authors.initials: L
authors.lastname: Giuffrida
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, 3010, Australia.
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Wood
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, 3010, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Gonsalvez
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, 3010, Australia.
authors.forename: Anita
authors.initials: A
authors.lastname: Ferner
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, 3010, Australia.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Kilpatrick
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, 3010, Australia.
authors.forename: Simon S
authors.initials: SS
authors.lastname: Murray
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, 3010, Australia.
authors.forename: Junhua
authors.initials: J
authors.lastname: Xiao
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D005727:Ganglia, Spinal / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB; C494960:Fyn protein, mouse; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn
keywords: BDNF; ERK; Fyn; MAPK; Src family kinase; myelination; oligodendrocyte