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The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans

Abstract

The C. elegans heterochronic gene pathway consists of a cascade of regulatory genes that are temporally controlled to specify the timing of developmental events1. Mutations in heterochronic genes cause temporal transformations in cell fates in which stage-specific events are omitted or reiterated2. Here we show that let-7 is a heterochronic switch gene. Loss of let-7 gene activity causes reiteration of larval cell fates during the adult stage, whereas increased let-7 gene dosage causes precocious expression of adult fates during larval stages. let-7 encodes a temporally regulated 21-nucleotide RNA that is complementary to elements in the 3′ untranslated regions of the heterochronic genes lin-14, lin-28, lin-41, lin-42 and daf-12, indicating that expression of these genes may be directly controlled by let-7. A reporter gene bearing the lin-41 3′ untranslated region is temporally regulated in a let-7-dependent manner. A second regulatory RNA, lin-4, negatively regulates lin-14 and lin-28 through RNA–RNA interactions with their 3′ untranslated regions3,4. We propose that the sequential stage-specific expression of the lin-4 and let-7 regulatory RNAs triggers transitions in the complement of heterochronic regulatory proteins to coordinate developmental timing.

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Figure 1: The let-7 heterochronic phenotype.
Figure 2: The let-7 gene sequence.
Figure 3: The 21-nucleotide let-7 RNA.
Figure 4: let-7 regulation of heterochronic genes.
Figure 5: A model for the successive regulation of heterochronic gene activities by the lin-4 and let-7 RNAs.

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Acknowledgements

We thank the C. elegans Genome Sequencing Consortium for sequence data, A. Coulson and the Sanger Centre for cosmids, the Caenorhabditis Genetics Center and V. Ambros for providing strains and sharing unpublished results. We thank R. Feinbaum for advice concerning experimental procedures and Y. Liu and P. Delerme for technical assistance. This work was supported by NIH grants to G.R., H.R.H. and A.R., and an NIH postdoctoral fellowship to F.S. H.R.H. is an Investigator of the Howard Hughes Medical Institute.

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Reinhart, B., Slack, F., Basson, M. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901–906 (2000). https://doi.org/10.1038/35002607

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