Abstract:

Myelin plays important roles in vertebrates, ensuring the rapid propagation of action potentials and the long-term integrity of axons, but the molecular mechanisms of myelin formation remain poorly understood. Recent studies have demonstrated that myelination is regulated by the TAM family of enzymes, which consists of Tyro3 (also known as Brt, Dtk, Rse, Sky, and Tif), Axl (also known as Ark, Tyro7, and Ufo), and Mer (also known as Eyk, Nym, and Tyro12) along with its ligand growth arrest-specific gene 6 (Gas6). The three TAMs are also expressed in the brain during postnatal development, specifically, in the white matter, which consists of myelinated axons (Prieto et al. 2000). These studies are helping to identify the signals that are associated with myelination in oligodendrocytes and Schwann cells. It is well established that TAMs control inflammatory responses, cell proliferation, cell survival, and phagocytosis in cells of various types. As their endogenous ligands, the TAMs recognize protein S (PROS1) and Gas6, both of which are widely expressed in the central nervous system (CNS) after birth. Interestingly, recent works have explained that Gas6 signaling controls oligodendrocyte survival through phosphatidylinositol 3-kinase (PI3-kinase) and upregulates the expression of 2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNPase), which is known as a marker for oligodendrocyte and myelin. It also plays an important role in oligodendrocyte myelination. These findings indicate that the TAM-Gas6 signaling pathway promotes the myelination of oligodendrocytes in the nervous system as well as supporting immune responses. Moreover, Gas6 also promotes the remyelination of oligodendrocytes after cuprizone-induced injury and is necessary for oligodendrocyte survival. Taken together, these findings demonstrate that the TAM-Gas6 signaling pathway plays an important role in myelination/remyelination and demyelination by oligodendrocytes in the CNS. Yet the molecular mechanisms operating within this pathway and underlying the myelin formation process during development remain largely unknown. This review summarizes recent developments in our understanding of the necessity of Gas6-stimulated Tyro3 activation for Schwann cell myelination and/or remyelination.