C. elegans LIN-28 controls temporal cell fate progression by regulating LIN-46 expression via the 5′ UTR of lin-46 mRNA

Lin28/LIN-28 is a conserved RNA-binding protein that promotes proliferation and pluripotency and can be oncogenic in mammals. Mammalian Lin28 and C. elegans LIN-28 have been shown to inhibit biogenesis of the conserved cellular differentiation-promoting microRNA let-7 by directly binding to unprocessed let-7 transcripts. Lin28/LIN-28 also bind and regulate many mRNAs in diverse cell types. However, the determinants and consequences of LIN-28-mRNA interactions are not well understood. Here, we report that C. elegans LIN-28 represses the expression of LIN-46, a downstream protein in the heterochronic pathway. We find that lin-28 and sequences within the lin-46 5′ UTR are required to prevent LIN-46 expression at early larval stages. Moreover, we find that precocious LIN-46 expression caused by mutations in the lin-46 5′ UTR is sufficient to cause precocious heterochronic defects similar to those of lin-28(lf) animals. Thus, our findings demonstrate the biological importance of the regulation of individual target mRNAs by LIN-28. [Display omitted] •An intact 5′ UTR of lin-46 is necessary to prevent precocious cell fate progression•LIN-28 and 5′ UTR of lin-46 prevent precocious LIN-46 expression•LIN-46 is expressed in the vulval precursor cells and stimulates vulva development Ilbay et al. characterize the role of the 5′ UTR of lin-46, a heterochronic gene in C. elegans and the critical mRNA target of the widely conserved RNA-binding protein LIN-28, demonstrating the importance of the regulation of mRNAs by LIN-28 in vivo along with the conserved microRNA let-7.