{"doi":"10.7916/d8-km9f-8n84","title":"Regulation of the LIN-12/Notch Core Nuclear Complex Components in Caenorhabditis elegans Reproductive Development","abstract":"LIN-12/Notch is a conserved transmembrane receptor that is required during animal development for proper cell-fate decisions and specification. In Caenorhabditis elegans, activation of LIN-12 occurs through binding to ligand expressed by an adjacent cell. This binding event triggers two cleavage steps and results in the release of the LIN-12 intracellular domain [LIN-12(intra)], which translocates to the nucleus to form a ternary complex with two other proteins: LAG-1/Su(H)/Cbf1 and SEL-8/Mastermind/Mastermind-like. This ternary complex will then transcriptionally activate target genes via LAG-1 Binding Sites (LBSs). LAG-1 is the sole DNA-binding component within the complex, and in the absence of LIN-12(intra), can act as a transcriptional repressor. LIN-12 signal transduction can be studied in the C. elegans Vulval Precursor Cells (VPCs), which exhibit precise spatiotemporal patterning regulated by LIN-12 activity. Here, I show that LAG-1 is positively autoregulated by LIN-12 activity in cells where LIN-12 activity is high. Autoregulation is mediated by an enhancer element that contains a cluster of 18 LBSs that are located within a conserved high occupancy target region, which is a span of DNA that is pulled down promiscuously in ChIP-Seq experiments. Mutation of the LBSs abrogates preferential expression mediated by the enhancer in cells with high LIN-12 signal transduction. When the HOT region is deleted from the endogenous lag-1 locus, expression in the VPCs is strongly reduced and no overt Lag phenotype occurs. Instead, cold-sensitive vulval and egg-laying defects, reminiscent of phenotypes seen in lin-12 hypomorphs, are found. Autoregulation of lag-1, therefore, appears to contribute to the robustness of LIN-12 cell fate specification in response to stochastic environmental and genetic perturbations. Under adverse environmental conditions, C. elegans enter a state of diapause in which they form dauer larvae, which are long-lived and stress-resistant. The VPCs of dauer larvae remain developmentally arrested indefinitely until favorable conditions are reintroduced. Experimentally, this arrest can be relieved by depletion of the Forkhead transcription factor DAF-16. I show that expression of the components of the LIN-12/SEL-8/LAG-1 ternary complex are downregulated during the L2d-dauer molt (prior to dauer entry) and that this downregulation is not relieved by DAF-16 depletion. Instead, DAF-16 depletion leads to resumption of LIN-12 signaling and expression of ternary complex only in completely formed dauer larvae. These observations suggest that DAF-16 is required for the maintenance but not the initiation of blocking LIN-12 signaling. The components of the ternary complex are required to effect LIN-12 signaling. This work contributes to better understanding how these components are regulated and how their expression can affect LIN-12 -mediated cell fate decisions.","journal":"Columbia Academic Commons (Columbia University)","year":2020,"id":131397,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9482,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":432224,"name":"Katherine L. Luo","orcid":"0000-0002-1509-5204","position":0,"is_corresponding":true}],"reference_count":112,"raw_metadata":null,"created_at":"2026-07-18T23:16:03.875886Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}