LIN-12/Notch Activation Leads to MicroRNA-Mediated Down-Regulation of Vav in C. elegans

• DOI: 10.1126/science.1119481
• Publication Date: 2005-10-26T07:33:44Z
• Authors: Andrew S. Yoo; Iva Greenwald
• Keywords: Feedback, Physiological; Receptors, Notch; Transcription, Genetic; Stem Cells; Computational Biology; Down-Regulation; Gene Expression Regulation, Developmental; Membrane Proteins; Regulatory Sequences, Nucleic Acid; Vulva; Animals, Genetically Modified; MicroRNAs; Animals; Female; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Proto-Oncogene Proteins c-vav; 3' Untranslated Regions; Genes, Helminth; Signal Transduction

Cell-cell interactions and cross-talk between signaling pathways specify Caenorhabditis elegans vulval precursor cells (VPCs) to adopt a spatial pattern: a central “1°” VPC, in which epidermal growth factor receptor (EGFR)–mitogen-activated protein kinase (MAPK) activity is high and LIN-12/Notch activity is low, flanked by two “2°” VPCs, in which LIN-12/Notch activity is high and EGFR-MAPK activity is low. Here, we identify a microRNA gene, mir-61 , as a direct transcriptional target of LIN-12 and show that expression of mir-61 promotes the 2° fate. We also identify vav-1 , the ortholog of the Vav oncogene, as a target of mir-61 , and show that down-regulation of VAV-1 promotes lin-12 activity in specifying the 2° fate. Our results suggest that lin-12, mir-61 , and vav-1 form a feedback loop that helps maximize lin-12 activity in the presumptive 2° VPCs.