Glial cell line–derived neurotrophic factor (GDNF) is a member of the GDNF family ligands (GFLs) and serves as both a long-distance trophic factor and a local trophic factor in various settings. Because neurons are highly polarized cells, retrograde transport to the cell body of trophic factors and their receptors allows signals detected by the distal axons to support cell survival and proliferation. GDNF does not undergo retrograde transport in all types of neurons in which its receptors are present. For example, GDNF is not retrogradely transported in sympathetic neurons of the superior cervical ganglion (SCG) but is retrogradely transported by some sensory neurons of the dorsal root ganglion (DRG). Tsui and Pierchala examined the mechanism underlying this difference and the functional consequences with a compartmentalized culture system that separates the extracellular space of the distal axons from that of the cell bodies. In this system, application of nerve growth factor (NGF) resulted in the retrograde transportation of the active form of its receptor in both types of neurons and supported survival of the neurons when applied to the distal axons. In contrast, GDNF applied to the distal axons only supported survival of the DRG neurons, not the SCG neurons. The phosphorylated and activated receptor for GDNF, Ret51, was detected in the distal axons exposed to GDNF for both DRG and SCG neurons; however, the abundance of phosphorylated and nonphosphorylated Ret51 decreased in the SGC neurons. For DRG neurons, active Ret51 remained detectable in both the distal axons and cell bodies even when GDNF was applied for 24 hours. Addition of a proteasome inhibitor along with GDNF to the distal axon compartment of the SCG cultures promoted survival as effectively as did application of GDNF directly to the cell bodies, and activated Ret51 was stabilized and detectable in the cell bodies. Multiple GDNF receptors may be present in neurons, and Ret51 and Ret9 were both detected in SCG and DRG neurons. Ret51 is known to be internalized and degraded more rapidly than Ret9, and SCG neurons had more Ret51 than Ret9, whereas Ret9 was more abundant than Ret51 in DRG neurons. SGC cultures from mice engineered to have only Ret9 showed that GDNF applied to the distal axons of these neurons promoted survival as effectively as did NGF. Thus, the difference in the proportions of Ret51 and Ret9, along with rapid degradation of Ret51 in the distal axons of SCG neurons, appears to allow GDNF to serve as a local signal for SCG neurons and a long-distance signal for DRG neurons.
C. C. Tsui, B. A. Pierchala, The differential axonal degradation of Ret accounts for cell-type-specific function of glial cell line-derived neurotrophic factor as a retrograde survival factor. J. Neurosci. 30, 5149–5158 (2010). [Abstract] [Full Text]