Severe hypomyelination of the murine CNS in the absence of myelin-associated glycoprotein and fyn tyrosine kinase.
The analysis of mice deficient in the myelin-associated glycoprotein (MAG) or Fyn, a nonreceptor-type tyrosine kinase proposed to act as a signaling molecule downstream of MAG, has revealed that both molecules are involved in the initiation of myelination. To obtain more insights into the role of the MAG-Fyn signaling pathway during initiation of myelination and formation of morphologically intact myelin sheaths, we have analyzed optic nerves of MAG-, Fyn- and MAG/Fyn-deficient mice. We observed a slight hypomyelination in optic nerves of MAG mutants that was significantly increased in Fyn mutants and massive in MAG/Fyn double mutants. The severe morphological phenotype of MAG/Fyn mutants, accompanied by behavioral deficits, substantiates the importance of both molecules for the initiation of myelination. The different severity of the phenotype of different genotypes indicates that the MAG-Fyn signaling pathway is complex and suggests the presence of compensatory mechanisms in the single mutants. However, data are also compatible with the possibility that MAG and Fyn act independently to initiate myelination. Hypomyelination of optic nerves was not related to a loss of oligodendrocytes, indicating that the phenotype results from impaired interactions between oligodendrocyte processes and axons and/or impaired morphological maturation of oligodendrocytes. Finally, we demonstrate that Fyn, unlike MAG, is not involved in the formation of ultrastructurally intact myelin sheaths.
Biffiger
K
K
Institute for Neurobiology, Federal Institute of Technology, Hönggerberg, CH-8093 Zürich, Switzerland.
Bartsch
S
S
Montag
D
D
Aguzzi
A
A
Schachner
M
M
Bartsch
U
U
D000818:Animals; D001369:Axons / Q000648:ultrastructure; D001522:Behavior, Animal; D002452:Cell Count; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000235:genetics / Q000648:ultrastructure*; D018992:Myelin-Associated Glycoprotein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D009900:Optic Nerve / Q000648:ultrastructure; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D015398:Signal Transduction / Q000235:genetics; D013116:Spinal Cord / Q000648:ultrastructure
D018992:Myelin-Associated Glycoprotein; D011518:Proto-Oncogene Proteins; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn