The TAM receptor TYRO3 is a critical regulator of myelin thickness in the central nervous system

The serine/threonine kinase Akt regulates multiple cellular functions. The current studies identify a new role for Akt in CNS myelination. In earlier studies on cultured oligodendrocytes, we showed that neuregulin signals through phosphatidylinositol-3'-OH kinase and Akt to enhance survival of oligodendrocytes. However, when transgenic animals were generated that overexpressed constitutively active Akt in oligodendrocytes and their progenitor cells, no enhanced survival of oligodendrocytes or progenitors was found. No alteration in the proliferation or death of progenitors was noted. In contrast, the major impact of Akt overexpression in oligodendrocytes was enhanced myelination. Most interestingly, oligodendrocytes in these mice continued actively myelinating throughout life. Thus, expression of constitutively active Akt in oligodendrocytes and their progenitor cells generated no more oligodendrocytes, but dramatically more myelin. The increased myelination continued as these mice aged, resulting in enlarged optic nerves and white matter areas. In older animals with enlarged white matter areas, the density of oligodendrocytes was reduced, but because of the increased area, the total number of oligodendrocytes remained comparable with wild-type controls. Interestingly, in these animals, overexpression of Akt in Schwann cells did not impact myelination. Thus, in vivo, constitutively active Akt enhances CNS myelination but not PNS myelination and has no impact developmentally on oligodendrocyte number. Understanding the unique aspects of Akt signal transduction in oligodendrocytes that lead to myelination rather than uncontrolled proliferation of oligodendrocyte progenitor cells may have important implications for understanding remyelination in the adult nervous system.

To study microglial/macrophage infiltration, a cuprizone-induced model for demyelination in C57BL/6 mice was established. Cuprizone is known to cause demyelination in Swiss mice, however, cuprizone-induced demyelination in C57BL/6 mice has not been previously described. Induction of demyelination in C57BL/6 mice enables examination of the function of microglia/macrophage through comparative analyses of syngeneic mice with various targeted genetic mutations. In this report, cuprizone-induced demyelination is easily inducible, localized, and predictable. Concurrent with the initiation of demyelination, we noted microglial/macrophage accumulation and changes in astrocyte morphology. Astrogliosis promptly followed microglia/macrophage recruitment. These observations suggested that microglia/macrophage actively contribute to the demyelination process.