Granulocyte macrophage colony-stimulating factor promotes regeneration of retinal ganglion cells in vitro through a mammalian target of rapamycin-dependent mechanism

Lack of regeneration in the adult central nervous system (CNS) is a major hurdle that limits recovery from neurological ailments. Although accumulating research suggests the possibility of axon regeneration by targeting intrinsic signaling mechanisms, it remains a matter of controversy whether functional recovery can be achieved by manipulating aspects of molecular signaling. Recent studies have shown that granulocyte macrophage colony-stimulating factor (GM-CSF) may be an effective means of targeting repair following CNS injury; how this molecule is able to produce this effect is not known. Indeed, GM-CSF has been shown to promote neuronal survival, potentially through activation of as yet unknown cytokine-dependent signals and potentially through regulation of antiapoptotic mechanisms. It is well established that the loss of intrinsic regenerative ability is highly correlated with development of CNS neurons. We therefore designed experiments, using a well-established in vitro retinal ganglion cell (RGC) culture system, to evaluate the effect of GM-CSF on axon growth and cell survival and define possible mechanisms involved in GM-CSF-mediated effects in vitro. Several developmental stages were evaluated, with particular focus placed on stages at which axon growth is known to be significantly diminished. Our results reveal that GM-CSF not only promotes axon growth in postnatal RGCs but also enhances cell survival through a mammalian target of rapamycin (mTOR)-dependent mechanism