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The Journal of Neuroscience, October 1, 2000, 20(19):7430-7437

Severe Hypomyelination of the Murine CNS in the Absence of Myelin-Associated Glycoprotein and Fyn Tyrosine Kinase

Karin Biffiger¹, Susanne Bartsch¹, Dirk Montag¹, Adriano Aguzzi², Melitta Schachner³, and Udo Bartsch^{1, 3}

¹ Institute for Neurobiology, Federal Institute of Technology, Hönggerberg, CH-8093 Zürich, Switzerland, ² Institute of Neuropathology, University Hospital of Zürich, CH-8091 Zürich, Switzerland, and ³ Zentrum für Molekulare Neurobiologie, Universität Hamburg, D-20246 Hamburg, Germany

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.

Key words: double knock-out mutant; hypomyelination; Fyn; MAG; oligodendrocyte; optic nerve; spinal cord

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20197430-08$05.00/0

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