Systematic Analyses of rpm-1 Suppressors Reveal Roles for ESS-2 in mRNA Splicing in Caenorhabditis elegans

摘要: The PHR (Pam/Highwire/RPM-1) family of ubiquitin E3 ligases plays conserved roles in axon patterning and synaptic development. Genetic modifier analysis has greatly aided the discovery signal transduction cascades regulated by these proteins. In Caenorhabditis elegans, loss function rpm-1 causes overgrowth aberrant presynaptic morphology, yet mutant animals exhibit little behavioral deficits. Strikingly, mutations strongly synergize with active zone assembly factors, syd-1 syd-2, resulting severe locomotor Here, we provide ultrastructural evidence that double mutants, between or dramatically impair synapse formation. Taking advantage synthetic defects to select for genetic suppressors, previous studies have identified DLK-1 MAP kinase cascade negatively RPM-1. We now report a comprehensive large number suppressor this screen. Our results highlight functional specificity synaptogenesis. also two previously uncharacterized genes. One encodes novel protein, SUPR-1, acts cell autonomously antagonize other affects protein ESS-2, homolog human ES2 DGCR14. Loss ess-2 suppresses only presence dlk-1 splice acceptor mutation. show ESS-2 promote accurate mRNA splicing when site is compromised. DGCR14/ES2 resides deleted chromosomal region implicated DiGeorge syndrome, its mutation shown high probability as risk factor schizophrenia. findings first proteins regulate context-specific manner.