Figure 4. Downregulation of Insulin/IGF-1-like signaling (IIS) prevents neuronal degeneration triggered by mec-4d.

(A) DAF-2 negatively regulates both DAF-16/FOXO and SKN-1/Nrf2, which by different mechanisms increases the cellular antioxidative capacity. (B–C) The possible protective role of the IIS pathway activation in mec-4d degeneration was explored in daf-2(e1370ts) mutants. At the restrictive temperature both somas (B) and axons (C) were significantly protected respect to the controls not carrying the mec-4d(e1611) mutation or daf-2(e1370ts) mutants carrying mec-4d(e1611) and raised at 20°C. Below each bar graph, a line graph incorporating only the SoW and AxW of daf-2;mec-4d vs. mec-4d raised at 25 °C is shown. Notice that mec-4d-dependent degeneration of both somas and axons is delayed for about one day at 25°C compared to 20°C (mean value for each category is shown; error bars [<0.1%] are not included; N = 3 of 30 worms each per group; ^#p<0.05 and *p<0.01 by Student's t test compared with control at the same temperature for the SoW and AxW category). (D–E) TRN-autonomous daf-2(RNAi) was performed in the P_mec-17mec-17::gfp strain carrying the mec-4d(e1611) mutation (WCH6). Significant morphological protection of both AVM somas (D) and axons (E) is seen at 72 hours post hatching (mean value for each category is shown; error bars [<0.1%] are not included; N = 3 of 30 worms each per group; *p<0.001 by Student's t test compared with control at the same temperature for the SoW and AxW category).