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 m olecule downstream of MAG, has revealed that both molecules are involved in the initiation of myelination. To obtain more insights into the role of th e 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 mut ants and massive in MAG/Fyn double mutants. The severe morphological phenot ype of MAG/Fyn mutants, accompanied by behavioral deficits, substantiates t he importance of both molecules for the initiation of myelination. The diff erent severity of the phenotype of different genotypes indicates that the M AG- Fyn signaling pathway is complex and suggests the presence of compensat ory mechanisms in the single mutants. However, data are also compatible wit h the possibility that MAG and Fyn act independently to initiate myelinatio n. Hypomyelination of optic nerves was not related to a loss of oligodendro cytes, indicating that the phenotype results from impaired interactions bet ween oligodendrocyte processes and axons and/or impaired morphological matu ration of oligodendrocytes. Finally, we demonstrate that Fyn, unlike MAG, i s not involved in the formation of ultrastructurally intact myelin sheaths.