The conserved neuronal F-box protein FSN-1 regulates neuromuscular junction development by negatively regulating DLK-mediated MAPK signaling in the presynaptic terminal (Liao et al., 2004; Nakata et al., 20005; Wu et al., 2007). We show here that attenuation of insulin/IGF signaling also contributes to FSN-1-dependent synaptic development and function. Loss of
fsn-1 leads to aberrant synapse growth and a significant decrease in spontaneous vesicle release frequency from the neuromuscular junctions. These synaptic defects are partially and specifically rescued by decreasing insulin/IGF signaling activity in postsynaptic muscles, as well as by reducing the activity of EGL-3, a proprotein convertase that processes neuronal agonistic insulin/IGF ligands INS-4 and INS-6. FSN-1 interacts with, and potentiates the ubiquitination of EGL-3 in vitro, and reduces the level of EGL-3 in vivo. A constitutively activated MAPK, MKK-4(DD), can revert the suppression effect of
fsn-1 by
daf-2, indicating that MAPK pathway may act genetically downstream of the insulin pathway. We propose that FSN-1 negatively regulates insulin/IGF signaling and MAPK pathways to coordinate synapse growth signals from both pre- and postsynaptic terminals. Liao, EH, Hung, W, Abrams, B, Zhen, M. (2004) Nature 430:345 Nakata, K, Abrams, B, Grill, B, Goncharov, A, Huang, X, Chisolm, A, Jin, Y (2005) Cell 120:407 Wu, C, Daniels, RW, DiAntonio, A (2007) Neural Dev. 2:16.