miRNAs cooperate in apoptosis regulation duringC. elegansdevelopment.
Programmed cell death occurs in a highly reproducible manner duringCaenorhabditis elegansdevelopment. We demonstrate that, during embryogenesis, miR-35 and miR-58bantamfamily microRNAs (miRNAs) cooperate to prevent the precocious death of mothers of cells programmed to die by repressing the geneegl-1, which encodes a proapoptotic BH3-only protein. In addition, we present evidence that repression ofegl-1is dependent on binding sites for miR-35 and miR-58 family miRNAs within theegl-13' untranslated region (UTR), which affect both mRNA copy number and translation. Furthermore, using single-molecule RNA fluorescent in situ hybridization (smRNA FISH), we show thategl-1is transcribed in the mother of a cell programmed to die and that miR-35 and miR-58 family miRNAs prevent this mother from dying by keeping the copy number ofegl-1mRNA below a critical threshold. Finally, miR-35 and miR-58 family miRNAs can also dampen the transcriptional boost ofegl-1that occurs specifically in a daughter cell that is programmed to die. We propose that miRNAs compensate for lineage-specific differences inegl-1transcriptional activation, thus ensuring that EGL-1 activity reaches the threshold necessary to trigger death only in daughter cells that are programmed to die.
Center for Integrated Protein Science Munich - CIPSM, Department Biology II, Ludwig-Maximilians-University Munich, Planegg-Martinsried 82152, Germany.
Ryan
R
Sherrard
Center for Integrated Protein Science Munich - CIPSM, Department Biology II, Ludwig-Maximilians-University Munich, Planegg-Martinsried 82152, Germany.
Sebastian
S
Luehr
Center for Integrated Protein Science Munich - CIPSM, Department Biology II, Ludwig-Maximilians-University Munich, Planegg-Martinsried 82152, Germany.
Heinke
H
Holzkamp
Program in Molecular Medicine, RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01606, USA.
Katherine
K
McJunkin
Center for Integrated Protein Science Munich - CIPSM, Department Biology II, Ludwig-Maximilians-University Munich, Planegg-Martinsried 82152, Germany.
Nadin
N
Memar
Center for Integrated Protein Science Munich - CIPSM, Department Biology II, Ludwig-Maximilians-University Munich, Planegg-Martinsried 82152, Germany.
Barbara
B
Conradt
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D019070:Cell Lineage; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype
D029742:Caenorhabditis elegans Proteins; C570417:MIRN35 microRNA, C elegans; D035683:MicroRNAs
BH3-only; C. elegans; development; embryo; miRNA; programmed cell death