Laminin Alters Fyn Regulatory Mechanisms and Promotes Oligodendrocyte Development

Abstract

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 kinasedependent 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.

Extracellular Matrix: Functions in the Nervous System

“…The degree of developmental delay is region-specific, which may reflect different laminin a2 requirements ). Abnormalities in Fyn signaling, which is modulated by laminins in cultured oligodendrocytes, were observed in the mutant brains, suggesting one explanation for the temporary stall in oligodendrocyte differentiation (Colognato et al 2004;Relucio et al 2009). Interestingly, b1 integrins not only affect PNS but also CNS myelination (Relvas et al 2001;Barros et al 2009).…”

“…Expression of laminins correlates with the onset of CNS myelination (Colognato et al 2002;Colognato et al 2005), and varied degrees of defects have been found in white matter tracts of patients suffering from MDC (Caro et al 1999;Leite et al 2005). Mice lacking laminin a2 have a developmental delay in oligodendrocyte maturation, resulting in hypomyelination (Chun et al 2003;Relucio et al 2009). The degree of developmental delay is region-specific, which may reflect different laminin a2 requirements ).…”

Wnt/Rspondin/β-catenin signals control axonal sorting and lineage progression in Schwann cell development

“…The identification of regulators of actin polymerization suggests a direct effect of Wnt signaling on SC process extension and lamellipodia formation. In particular, Fyn kinase has been shown to control cytoskeletal modifications and lamellae extension in oligodendrocytes (44,45). The identified transcription factors could also directly affect SC differentiation: Jun is a known negative regulator of SC differentiation and myelination (2,46).…”

Inhibition of Myelin Membrane Sheath Formation by Oligodendrocyte-derived Exosome-like Vesicles

“…exo, exosomes. (26,(33)(34)(35)(36)(37)(38). We used the small molecular inhibitor PP2 to find out whether NCM increase oligodendrocytes cell surface area in a Src kinase-dependent manner.…”