LIN-12/Notch activation leads to microRNA-mediated down-regulation of Vav in C. elegans.
Cell-cell interactions and cross-talk between signaling pathways specify Caenorhabditis elegans vulval precursor cells (VPCs) to adopt a spatial pattern: a central "1 degrees " 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 degrees " 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 degrees 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 degrees 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 degrees VPCs.
Yoo
Andrew S
AS
Integrated Program in Cellular, Molecular, and Biophysical Studies, Howard Hughes Medical Institute, Columbia University College of Physicians and Surgeons, 701 West 168th Street, Room 720, New York, NY 10032, USA.
Greenwald
Iva
I
D020413:3' Untranslated Regions; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D019295:Computational Biology; D015536:Down-Regulation; D025461:Feedback, Physiological; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017238:Genes, Helminth; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics* / Q000378:metabolism; D051880:Receptors, Notch; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014158:Transcription, Genetic; D014844:Vulva / Q000166:cytology / Q000254:growth & development
D020413:3' Untranslated Regions; D029742:Caenorhabditis elegans Proteins; C082460:Lin-12 protein, C elegans; D008565:Membrane Proteins; D035683:MicroRNAs; D051567:Proto-Oncogene Proteins c-vav; D051880:Receptors, Notch; C505656:VAV-1 protein, C elegans