Laminin alters fyn regulatory mechanisms and promotes oligodendrocyte development.
Mutations in LAMA2, the gene for the extracellular matrix protein laminin-alpha2, 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.
Department of Pharmacology, Stony Brook University, New York 11794, USA.
Jenne
J
Relucio
Iva D
ID
Tzvetanova
Wei
W
Ao
Sabine
S
Lindquist
Holly
H
Colognato
D000818:Animals; D001921:Brain / Q000254:growth & development* / Q000502:physiology* / Q000648:ultrastructure; D000081247:CSK Tyrosine-Protein Kinase; D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000502:physiology / Q000648:ultrastructure; D009836:Oligodendroglia / Q000502:physiology* / Q000648:ultrastructure; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology; D019061:src-Family Kinases
D007797:Laminin; D008565:Membrane Proteins; C498709:Pag1 protein, mouse; C408142:Pag1 protein, rat; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; C494960:Fyn protein, mouse; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases