Stage-Specific Timing of the microRNA Regulation of lin-28 by the Heterochronic Gene lin-14 in Caenorhabditis elegans.
In normal development, the order and synchrony of diverse developmental events must be explicitly controlled. In the nematode Caenorhabditis elegans, the timing of larval events is regulated by hierarchy of proteins and microRNAs (miRNAs) known as the heterochronic pathway. These regulators are organized in feedforward and feedback interactions to form a robust mechanism for specifying the timing and execution of cell fates at successive stages. One member of this pathway is the RNA binding protein LIN-28, which promotes pluripotency and cell fate decisions in successive stages. Two genetic circuits control LIN-28 abundance: it is negatively regulated by the miRNA lin-4, and positively regulated by the transcription factor LIN-14 through a mechanism that was previously unknown. In this report, we used animals that lack lin-4 to elucidate LIN-14's activity in this circuit. We demonstrate that three let-7 family miRNAs-miR-48, miR-84, and miR-241-inhibit lin-28 expression. Furthermore, we show genetically that these miRNAs act between lin-14 and lin-28, and that they comprise the pathway by which lin-14 positively regulates lin-28 We also show that the lin-4 family member mir-237, also regulates early cell fates. Finally, we show that the expression of these miRNAs is directly inhibited by lin-14 activity, making them the first known targets of lin-14 that act in the heterochronic pathway.
Department of Molecular Biology, Rowan University, Stratford, New Jersey 08084.
Jennifer
J
Tsialikas
Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin 53233.
Mitchell A
MA
Romens
Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin 53233.
Allison
A
Abbott
Department of Molecular Biology, Rowan University, Stratford, New Jersey 08084 mosseg@rowan.edu.
Eric G
0000-0002-0113-6618
EG
Moss
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D007814:Larva / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
D029742:Caenorhabditis elegans Proteins; C102669:LIN-14 protein, C elegans; C452195:LIN-28 protein, C elegans; D035683:MicroRNAs; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C474488:let-7 microRNA, C elegans; C452194:lin-4 microRNA, C elegans
C. elegans; LIN-14; LIN-28; heterochronic genes; let-7; microRNA