Helping to Start and Stop Myelination: Csk has Dual Regulatory Functions during Oligodendrocyte Development

Abstract

The ability of oligodendrocyte progenitors (OPCs) to generate sufficient numbers of myelinating oligodendrocytes is critical both for developmental myelination and for repair following demyelination. The timing and location of gliogenesis are tightly controlled but the molecular mechanisms that underlie this control are poorly understood. Here I report that the C-terminal Src Kinase (Csk) acts as a molecular switch for Src Family Kinase activity in oligodendrocytes, with distinct and opposing roles for Csk in early versus late stages of development. Early in development Csk is critical for the appropriate onset of oligodendrocyte progenitor differentiation. Csk suppresses OPC proliferation such that Csk depletion in OPCs in vitro and in vivo led to proliferation under conditions that normally promoted cell cycle exit. Hyperproliferation of Csk-deficient OPCs resulted in delayed oligodendrocyte maturation accompanied by delayed myelination onset, while survival of newly-formed oligodendrocytes was increased. These data suggest that, during myelination onset, Csk is a pro-differentiation factor that promotes timely OPC cell cycle exit. Adult Csk null mice, however, developed hypermyelination, suggesting that Csk also contributes to myelination arrest. Thus, Csk deletion caused increased levels of myelin basic protein as well as increased myelination in the cortex, cerebellum and spinal cord, although there was no change in the number of mature oligodendrocytes. Further analysis of myelin ultrastructure using transmission electron microscopy revealed increased numbers of myelin wraps such that the g-ratio was significantly decreased. To address a putative role for Csk during myelin repair I evaluated the response of Csk null mice to cuprizone-induced demyelination. Preliminary analyses reveal that during remyelination Csk mutant animals exhibit increased numbers of OPCs and mature oligodendrocytes, increased myelin content, and lower g-ratio as well as decreased axonal degeneration. I, therefore, propose that Csk is a novel regulator of oligodendrocyte development with two distinct roles: generating appropriate numbers of oligodendrocytes at the onset of myelination, and terminating wrapping during myelination.