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Letters to Nature

Nature 403, 901-906 (24 February 2000) | doi:10.1038/35002607; Received 7 October 1999; Accepted 6 December 1999

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

Brenda J. Reinhart1,2, Frank J. Slack1,2,3, Michael Basson3,4, Amy E. Pasquinelli1, Jill C. Bettinger3,7, Ann E. Rougvie7, H. Robert Horvitz4 & Gary Ruvkun1

  1. Department of Molecular Biology, Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA
  2. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
  3. Department of Genetics, Cell Biology and Development, University of Minnesota, St Paul, Minnesota 55108, USA
  4. These authors contributed equally to this work
  5. Present addresses: Axys Pharmaceuticals , South San Francisco, California 94080, USA (M.B.); Ernest Gallo Clinic and Research Center, UCSF, Emeryville, California 94608, USA (J.C.B.); Department of MCDB, Yale University, New Haven CT 06520 , USA (F.J.S.).

Correspondence to: Gary Ruvkun1 Correspondence and requests for materials should be addressed to G.R.

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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.