Misexpression of the Caenorhabditis elegans miRNA let-7 Is Sufficient to Drive Developmental Programs

Abstract

The Caenorhabditis elegans microRNAs (miRNAs) lin-4 and let-7 promote transitions between stage-specific events in development by down-regulating the translation of their target genes. Expression of let-7 is required at the fourth larval stage for the proper transition from larval to differentiated, adult fates in the hypodermis; however, it was not known whether expression of let-7 is sufficient to specify these adult fates. To test this, we created fusion genes between lin-4 and let-7 that direct the expression of let-7 two stages early, at the L2 stage. We find that animals bearing the fusion genes show precocious adult development at the L4 stage, indicating that temporal misexpression of let-7 is sufficient to direct the larval-to-adult transition. Additionally, an RNA interference (RNAi)-based screen for enhancers of the precocious phenotype identified the period ortholog lin-42, among other genes, which are candidate modulators of the effects of let-7 expression. let-7 is conserved throughout bilaterian phylogeny, and orthologs of its targets have roles in vertebrate development, suggesting the importance of understanding how let-7 promotes terminal differentiation in C. elegans and other organisms.

The role of let-7 in cell differentiation and cancer

“…Studies manipulating let-7 expression have confirmed the essential role of let-7 in the transition from larval 4 stage to adult stage. Fusing the let-7 gene to the lin-4 gene and directing let-7 expression at larval stage 2 was shown to lead to precocious adult development at L4 stage, demonstrating that expression of let-7 is sufficient to specify adult fate in the worm (Hayes & Ruvkun 2006).…”

Let-7 Prevents Early Cancer Progression by Suppressing Expression of the Embryonic Gene HMGA2

“…11,36 Its essential role in this process was demonstrated by missexpressing let-7 at L2 and causing a precocious L4 transition in the worm. 49 If the model of reversed embryogenesis is correct, then an embryonic gene that is downregulated at the late stages of embryonic development would be expected to be one of the first genes that is reactivated during cancer development. Let-7 regulated genes are therefore good candidates for markers of early tumor progression.…”

LEP-2/Makorin regulates LIN-28 stability to promote the juvenile-to-adult transition in Caenorhabditis elegans

“…LIN-28 inhibits the biogenesis of the mature form of the let-7 microRNA (miRNA) (Newman et al, 2008;Piskounova et al, 2008;Van Wynsberghe et al, 2011;Viswanathan et al, 2008). When LIN-28 is downregulated, mature let-7 miRNA is produced, directing cells toward differentiated/adult fates (Copley et al, 2013;Hayes and Ruvkun, 2006;Rybak et al, 2008;Thornton and Gregory, 2012;Tsialikas and Romer-Seibert, 2015;Yu et al, 2007) by inhibiting the translation of primarily lin-41 and other target mRNAs (Ecsedi and Grosshans, 2013;Long et al, 2007;Slack et al, 2000;Vella et al, 2004a,b). homologs are proposed to silence the translation of target mRNAs (Ecsedi and Grosshans, 2013;Ecsedi et al, 2015;Loedige et al, 2013;Sonoda and Wharton, 2001;Vella et al, 2004a,b) that otherwise promote an undifferentiated/juvenile state (Chang et al, 2012;Ecsedi and Grosshans, 2013;Rybak et al, 2009).…”