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


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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  1. Ambros, V. A hierarchy of regulatory genes controls a larva-to-adult developmental switch in C. elegans. Cell 57, 49– 59 (1989).

    Article  CAS  Google Scholar 

  2. Ambros, V. & Horvitz, H. R. Heterochronic mutants of the nematode Caenorhabditis elegans. Science 226 , 409–416 (1984).

    Article  ADS  CAS  Google Scholar 

  3. Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 ( 1993).

    Article  CAS  Google Scholar 

  4. Moss, E. G., Lee, R. C. & Ambros, V. The cold shock domain protein LIN-28 controls developmental timing in C. elegans and is regulated by the lin-4 RNA. Cell 88, 637–646 ( 1997).

    Article  CAS  Google Scholar 

  5. Meneely, P. M. & Herman, R. K. Lethals, steriles, and deficiencies in a region of the X chromosome of Caenorhabditis elegans. Genetics 92, 99–115 ( 1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Sulston, J. E. & Horvitz, H. R. Post-embryonic cell lineages of the nematode Caenorhabditis elegans. Dev. Biol 56, 110–156 (1977).

    Article  CAS  Google Scholar 

  7. Rougvie, A. E. & Ambros, V. The heterochronic gene lin-29 encodes a zinc finger protein that controls a terminal differentiation event in Caenorhabditis elegans. Development 121, 2491–2500 (1995).

    CAS  PubMed  Google Scholar 

  8. Bettinger, J. C., Lee, K. & Rougvie, A. E. Stage-specific accumulation of the terminal differentiation factor LIN-29 during Caenorhabditis elegans development. Development 122, 2517–2527 (1996).

    CAS  PubMed  Google Scholar 

  9. Liu, Z. Genetic Control of Stage-Specific Developmental Events in C. elegans. Thesis, Harvard Univ. (1990).

    Google Scholar 

  10. Abrahante, J. E., Miller, E. A. & Rougvie, A. E. Identification of heterochronic mutants in Caenorhabditis elegans: temporal misexpression of a collagen::green fluorescent protein fusion gene. Genetics 149, 1335– 1351 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kennedy, B. P. et al. The gut esterase gene (ges-1) from the nematodes Caenorhabditis elegans and Caenorhabditis briggsae. J. Mol. Biol. 229, 890–908 (1993).

    Article  CAS  Google Scholar 

  12. Zucker-Sparison, E. & Blumenthal, T. Potential regulatory elements of nematode vitellogenin genes revealed by interspecies sequence comparison. J. Mol. Evol. 28, 487– 496 (1989).

    Article  ADS  Google Scholar 

  13. Wightman, B. et al. Negative regulatory sequences in the lin-14 3′-untranslated region are necessary to generate a temporal switch during Caenorhabditis elegans development. Genes. Dev. 5, 1813–1824 (1991).

    Article  CAS  Google Scholar 

  14. Yeh, W. H. Genes Acting Late in the Signaling Pathway for Caenorhabditis elegans Dauer Larval Development. Ph.D. Thesis. University of Missouri, Columbia, MO (1991).

  15. Jeon, M., Gardner, H. F., Miller, E. A., Deshler, J. & Rougvie, A. E. Similarity of the C. elegans developmental timing protein LIN-42 to circadian rhythm proteins. Science 286, 1141–1146 ( 1999).

    Article  CAS  Google Scholar 

  16. Wightman, B., Ha, I. & Ruvkun, G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75, 855–862 ( 1993).

    Article  CAS  Google Scholar 

  17. Feinbaum, R. & Ambros, V. The timing of lin-4 RNA accumulation controls the timing of postembryonic developmental events in C. elegans . Dev. Biol. 210, 87– 95 (1999).

    Article  CAS  Google Scholar 

  18. Trent, C., Tsung, N. & Horvitz, H. R. Egg-laying defective mutants of the nematode Caenorhabditis elegans. Genetics 104, 619–647 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Segalat, L., Elkes, D. A. & Kaplan, J. M. Modulation of serotonin-controlled behaviors by G o in Caenorhabditis elegans. Science 267 , 1648–1651 (1995).

    Article  ADS  CAS  Google Scholar 

  20. Ausubel, F. M. et al. Current Protocols in Molecular Biology (John Wiley & Sons, New York, 1995).

    Google Scholar 

  21. Devereux, J., Haeberli, P. & Smithies, O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 12, 387– 395 (1984).

    Article  CAS  Google Scholar 

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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).

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