ABSTRACT
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.
Subject(s)
Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans/genetics , Nuclear Proteins/genetics , Repressor Proteins/genetics , Animals , Caenorhabditis elegans Proteins/metabolism , Cell Differentiation/genetics , Gene Expression Regulation, Developmental , Larva/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Nuclear Proteins/metabolism , RNA-Binding Proteins/genetics , Repressor Proteins/metabolism , Transcription Factors/geneticsABSTRACT
LIN28 is an RNA-binding protein that is best known for its roles in promoting pluripotency via regulation of the microRNA let-7. However, recent studies have uncovered new roles for LIN28 and have revealed how it functions, suggesting that it is more than just a regulator of miRNA biogenesis. Together, these findings imply a new paradigm for LIN28 - as a gatekeeper molecule that regulates the transition between pluripotency and committed cell lineages, in both let-7-dependent and let-7-independent manners. Here, we provide an overview of LIN28 function in development and disease.