DRE-1: An Evolutionarily Conserved F Box Protein that Regulates C. elegans Developmental Age

During metazoan development, cells acquire both positional and temporal identities. The Caenorhabditis elegans heterochronic loci are global regulators of larval temporal fates. Most encode conserved transcriptional and transla- tional factors, which affect stage-appropriate programs in various tissues. Here, we describe dre-1, a heterochronic gene, whose mutant phenotypes include precocious terminal differ- entiation of epidermal stem cells and altered temporal patterning of gonadal outgrowth. Ge- netic interactions with other heterochronic loci place dre-1 in the larval-to-adult switch. dre-1 encodes a highly conserved F box protein, sug- gesting a role in an SCF ubiquitin ligase com- plex. Accordingly, RNAi knockdown of the C. elegans SKP1-like homolog SKR-1, the cullin CUL-1, and ring finger RBX homologs yielded similar heterochronic phenotypes. DRE-1 and SKR-1 form a complex, as do the human ortho- logs, hFBXO11 and SKP1, revealing a phyleti- cally ancient interaction. The identification of core components involved in SCF-mediated modification and/or proteolysis suggests an important level of regulation in the hetero- chronic hierarchy.