Morphological Differentiation of Oligodendrocytes Requires Activation of Fyn Tyrosine Kinase

Abstract

In the central nervous system, myelination of axons occurs when oligodendrocyte progenitors undergo terminal differentiation and initiate process formation and axonal ensheathment. Although it is hypothesized that neuron-oligodendrocyte contact initiates this process, the molecular signals are not known. Here we find that Fyn tyrosine kinase activity is upregulated very early during oligodendrocyte progenitor cell differentiation. Concomitant with this increase is the appearance of several tyrosine phosphorylated proteins present only in differentiated cells. The increased tyrosine kinase activity is specific to Fyn, as other Src family members are not active in oligodendrocytes. To investigate the function of Fyn activation on differentiation, we used Src family tyrosine kinase inhibitors, PP1 and PP2, in cultures of differentiating oligodendrocyte progenitors. Treatment of progenitors with these compounds prevented activation of Fyn and reduced process extension and myelin membrane formation. This inhibition was reversible and not observed with related inactive analogues. A similar effect was observed when a dominant negative Fyn was introduced in progenitor cells. These findings strongly suggest that activation of Fyn is an essential signaling component for the morphological differentiation of oligodendrocytes.

Myelin associated glycoprotein cross-linking triggers its partitioning into lipid rafts, specific signaling events and cytoskeletal rearrangements in oligodendrocytes

“…Fyn is a member of the Src family of kinases and is associated with cell adhesion, migration, proliferation, differentiation, apoptosis and cytoskeletal rearrangements (Osterhout et al, 1999). Increased phosphorylation of Fyn following MAG cross-linking in double-transfected COS cells has been reported previously (Umemori et al, 1994;Umemori et al, 1999).…”

Rafts in oligodendrocytes: Evidence and structure–function relationship

“…Fyn is a key molecule in OLG differentiation and myelination (Osterhout et al, 1999;Sperber and McMorris, 2001;Umemori et al, 1994). This molecule belongs to the Src (Rous sarcoma) family of kinases and is associated with cell migration, proliferation, differentiation, adhesion, apoptosis and cytoskeletal rearrangements (Osterhout et al, 1999).…”

“…This molecule belongs to the Src (Rous sarcoma) family of kinases and is associated with cell migration, proliferation, differentiation, adhesion, apoptosis and cytoskeletal rearrangements (Osterhout et al, 1999). …”

Abnormal myelination in the spinal cord of PTPα-knockout mice

“…8 Hypomyelination of the optic nerve is significantly increased by ~40-50% in Fyn-deficient mice and by ~80% in MAG/ Fyn-deficient mice. 21,22 PTPα is a physiological activator of Fyn as demonstrated by the 60% reduced kinase activity of Fyn in brains of PTPα-deficient mice compared with WT mice.…”

“…7 Given that F3 is located at paranodes and promotes oligodendrocyte maturation as well as acts as a binding partner of PTPα, and that Fyn is implicated in oligodendrocyte differentiation and myelination, [8][9][10] we hypothesized that PTPα might be involved in modulating paranodal formation and myelination during CNS development. In this study, we found that PTPα was mainly expressed in both neurons and oligodendrocytes.…”