A unique role for Fyn in CNS myelination.
We analyzed the role of Fyn tyrosine kinase in CNS myelination by using fyn(-/-) null mutant mice, which express no Fyn protein. We found a severe myelin deficit in forebrain at all ages from 14 d to 1 year. The deficit was maximal at 1 month of age and was similar regardless of mouse strain background or whether it was determined by bulk isolation of myelin or by quantitation of myelin basic protein. To determine the cellular basis of the myelin deficit, we counted oligodendrocytes in tissue sections of mice expressing oligodendrocyte-targeted beta-galactosidase, and we used light and electron microscopy to examine the number and morphology of myelinated fibers and size of myelinated CNS structures. All of these parameters were reduced in fyn(-/-) mice. Unexpectedly, there were regional differences in the myelin deficit; in contrast to forebrain, fyn(-/-) cervical spinal cord exhibited no reduction in myelin content, number of oligodendrocytes, or number of myelinated fibers, nor was myelination delayed developmentally. We found that oligodendrocytes express Src, but there was no significant reduction of myelin content in null mutants lacking the Fyn-related kinases Src, Yes, or Lyn. Finally, we investigated the molecular features of Fyn that are required for myelination and found that a single amino acid substitution, which abolishes the tyrosine kinase activity of Fyn, resulted in a myelin deficit as great as that observed in the complete absence of Fyn protein. These results demonstrate that Fyn plays a unique role in myelination, one that requires its kinase activity.
The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
B R
BR
Sperber
E A
EA
Boyle-Walsh
M J
MJ
Engleka
P
P
Gadue
A C
AC
Peterson
P L
PL
Stein
S S
SS
Scherer
F A
FA
McMorris
D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D002478:Cells, Cultured; D002490:Central Nervous System / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D003337:Corpus Callosum / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017930:Genes, Reporter; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D016548:Prosencephalon / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D051575:Proto-Oncogene Proteins c-yes; D013116:Spinal Cord / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D004676:Myelin Basic Protein; D011518:Proto-Oncogene Proteins; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051575:Proto-Oncogene Proteins c-yes; C496639:Yes1 protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases