The Journal of Neuroscience, September 23, 2009, 29(38):11794-11806; doi:10.1523/JNEUROSCI.0888-09.2009
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Cellular/Molecular
Laminin Alters Fyn Regulatory Mechanisms and Promotes Oligodendrocyte Development
Jenne Relucio,1
Iva D. Tzvetanova,1
Wei Ao,1
Sabine Lindquist,2,3 and
Holly Colognato1
1Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794, 2Department of Neurology, Otto-von-Guericke University, 39120 Magdeburg, Germany, and 3Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany
Correspondence should be addressed to Holly Colognato, Department of Pharmacology, Stony Brook University, Stony Brook, NY 11794. Email: colognato{at}pharm.stonybrook.edu
Mutations in LAMA2, the gene for the extracellular matrix protein laminin-
2, cause a severe muscular dystrophy termed congenital muscular dystrophy type-1A (MDC1A). MDC1A patients have accompanying CNS neural dysplasias and white matter abnormalities for which the underlying mechanisms remain unknown. Here, we report that in laminin-deficient mice, oligodendrocyte development was delayed such that oligodendrocyte progenitors accumulated inappropriately in adult brains. Conversely, laminin substrates were found to promote the transition of oligodendrocyte progenitors to newly formed oligodendrocytes. Laminin-enhanced differentiation was Src family kinase-dependent and resulted in the activation of the Src family kinase Fyn. In laminin-deficient brains, however, increased Fyn repression was accompanied by elevated levels of the Src family kinase negative regulatory proteins, Csk (C-terminal Src kinase), and its transmembrane adaptor, Cbp (Csk-binding protein). These findings indicate that laminin deficiencies delay oligodendrocyte maturation by causing dysregulation of signaling pathways critical for oligodendrocyte development, and suggest that a normal role for CNS laminin is to promote the development of oligodendrocyte progenitors into myelin-forming oligodendrocytes via modulation of Fyn regulatory molecules.
Received Feb. 20, 2009;
revised Aug. 3, 2009;
accepted Aug. 7, 2009.
Correspondence should be addressed to Holly Colognato, Department of Pharmacology, Stony Brook University, Stony Brook, NY 11794. Email: colognato{at}pharm.stonybrook.edu
