TY - JOUR
T1 - Stage-specific timing of the microRNA regulation of lin-28 by the heterochronic gene lin-14 in Caenorhabditis elegans
AU - Tsialikas, Jennifer
AU - Romens, Mitchell A.
AU - Abbott, Allison
AU - Moss, Eric G.
N1 - Funding Information: Work in EGM’s lab supported by NSF IOS-0924497. Work in AA’s lab suported by NIH R15 GM084451. The authors thank Ron Ellis, Kevin Kemper, and Maddy Minutillo for advice and critical comments. Publisher Copyright: © 2017 by the Genetics Society of America.
PY - 2017/1
Y1 - 2017/1
N2 - 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.
AB - 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.
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U2 - https://doi.org/10.1534/genetics.116.195040
DO - https://doi.org/10.1534/genetics.116.195040
M3 - Article
C2 - 27815363
SN - 0016-6731
VL - 205
SP - 251
EP - 262
JO - Genetics
JF - Genetics
IS - 1
ER -