Presynaptic terminals are highly specialized subcellular structures to facilitate neurotransmitter release. In a presynaptic terminal, synaptic vesicles are docked at the vicinity of the active zone, an electron dense structure at the presynaptic plasma membrane. The periactive zone surrounds the vesicle clustering and active zone region. In
rpm-1</span><span lang=EN-US style='color:black'> mutants, the presynaptic terminals at the GABAergic neuromuscular junctions are disorganized (Zhen et al., 2000). RPM-1 is a member of the PHR protein family that includes Drosophila</span><span lang=EN-US style='color:black'> Highwire, Mammalian Phr and Pam, and is localized to the periactive zone. RPM-1 and its functional partner FSN-1 are components of an SCF-like E3 ubiquitin ligase (Liao et al., 2004).By isolating genetic suppressor mutations of
rpm-1, </span><span lang=EN-US style='color:black'>we have identified a
p38 MAP kinase pathway composed of the MAPKKK DLK-1, the MAPKK MKK-4, and the
p38 MAP kinase PMK-3 (Nakata et al., 2005). Inactivation of this pathway strongly suppresses
rpm-1</span><span lang=EN-US style='color:black'> loss of function phenotypes, whereas overexpression or constitutive activation of this pathway causes synaptic defects resembling
rpm-1</span><span lang=EN-US style='color:black'>(lf) mutants. DLK-1 appears to be localized to the periactive zone. Our biochemical studies support a mechanism by which RPM-1 controls the abundance of DLK-1 protein to down regulate the
p38 MAP kinase pathway. To explore additional signaling components involved in the DLK-1-MKK-4-PMK-3 pathway, we are continuing to analyze other suppressor mutations, while performing new genetic screens.We have previously performed an enhancer screen of
rpm-1</span><span lang=EN-US style='color:black'>, in which we found that null mutation of
mig-2</span><span lang=EN-US style='color:black'>, which encodes RhoG GTPase, enhances
rpm-1</span><span lang=EN-US style='color:black'>.
unc-73, </span><span lang=EN-US style='color:black'>a known upstream guanine nucleotide exchange factor of
mig-2,</span><span lang=EN-US style='color:black'> also enhances
rpm-1</span><span lang=EN-US style='color:black'>. We are addressing whether MIG-2 may be involved in DLK-1-
p38 MAP kinase signaling cascade.Nakata, K. et al. Cell, 120: 407-420, 2005Liao, E. H. et al. Nature, 430: 345-350, 2004Zhen, M. et al. Neuron, 26: 331-343, 2000