Physiological functions of the small GTPase Arf6 in the nervous system

Abstract

The small GTPase ADP-ribosylation factor 6 (Arf6) plays important roles in membrane dynamics-based neuronal cell events such as neurite outgrowth and spine formation. However, physiological functions of Arf6 in the nervous system at whole animal level have not yet been explored. We have recently generated conditional knockout mice lacking Arf6 in neurons or oligodendrocytes of central nervous system (CNS) or both cell lineages, and analyzed them. We found that ablation of Arf6 gene from neurons, but not from oligodendrocytes, caused the defect in axon myelination at the fimbria of hippocampus (Fim) and corpus callosum (CC). We also found that migration of oligodendrocyte precursor cells (OPCs) from the subventricular zone to the Fim and CC in mice lacking Arf6 in neurons was impaired. Finally, it was found that secretion of fibroblast growth factor-2 (FGF-2), a guidance factor for OPC migration, from hippocampi lacking Arf6 was impaired. Collectively, these findings demonstrate that Arf6 in neurons of the CNS plays an important role in OPC migration by regulating secretion of FGF-2 from neurons, thereby contributing to the axon myelination. Here, we discuss our current understanding of physiological functions of Arf6 in the nervous system.

Keywords: Arf6; FGF-2; conditional knockout mice; migration; myelination; neurons; oligodendrocytes.

Figure 1.

Schematic model for trans-regulation of OPC migration and axon myelination by neuronal Arf6. OPCs derived from the neural stem cells in the ventricular zone migrate to the target tissues, the Fim and CC, in response to FGF-2 secreted from neurons in an Arf6-dependent manner. In the Fim and CC, OPCs mature into oligodendrocytes which in turn form myelin sheaths.