Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The microRNA miR-235 couples blast-cell quiescence to the nutritional state


The coordination of stem- and blast-cell behaviours, such as self-renewal, differentiation and quiescence, with physiological changes underlies growth, regeneration and tissue homeostasis1,2,3. Germline stem and somatic blast cells in newly hatched Caenorhabditis elegans larvae can suspend postembryonic development, which consists of diverse cellular events such as migration, proliferation and differentiation, until the nutritional state becomes favourable (termed L1 diapause4,5,6). Although previous studies showed that the insulin/insulin-like growth factor (IGF) signalling (IIS) pathway regulates this developmental quiescence5,6,7,8, the detailed mechanism by which the IIS pathway enables these multipotent cells to respond to nutrient availability is unknown. Here we show in C. elegans that the microRNA (miRNA) miR-235, a sole orthologue of mammalian miR-92 from the oncogenic miR-17-92 cluster9,10, acts in the hypodermis and glial cells to arrest postembryonic developmental events in both neuroblasts and mesoblasts. Expression of mir-235 persists during L1 diapause, and decreases upon feeding in a manner dependent on the IIS pathway. Upregulation of one of the miR-235 targets, nhr-91, which encodes an orthologue of mammalian germ cell nuclear factor, is responsible for defects caused by loss of the miRNA. Our findings establish a novel role of a miR-92 orthologue in coupling blast-cell behaviours to the nutritional state.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: mir-235 is required for suppressing blast-cell reactivation and other postembryonic developmental events during starvation-induced L1 diapause.
Figure 2: mir-235 acts in the hypodermis and glia.
Figure 3: Expression of mir-235 is negatively regulated by feeding via the IIS pathway.
Figure 4: nhr-91 mRNA is a target of miR-235.


  1. Jasper, H. & Jones, D. L. Metabolic regulation of stem cell behavior and implications for aging. Cell Metab. 12, 561–565 (2010)

    CAS  Article  Google Scholar 

  2. Ables, E. T. & Drummond-Barbosa, D. Food for thought: neural stem cells on a diet. Cell Stem Cell 8, 352–354 (2011)

    CAS  Article  Google Scholar 

  3. Nakada, D., Levi, B. P. & Morrison, S. J. Integrating physiological regulation with stem cell and tissue homeostasis. Neuron 70, 703–718 (2011)

    CAS  Article  Google Scholar 

  4. Hong, Y., Roy, R. & Ambros, V. Developmental regulation of a cyclin-dependent kinase inhibitor controls postembryonic cell cycle progression in Caenorhabditis elegans. Development 125, 3585–3597 (1998)

    CAS  Article  Google Scholar 

  5. Fukuyama, M., Rougvie, A. E. & Rothman, J. H. C. elegans DAF-18/PTEN mediates nutrient-dependent arrest of cell cycle and growth in the germline. Curr. Biol. 16, 773–779 (2006)

    CAS  Article  Google Scholar 

  6. Baugh, L. R. & Sternberg, P. W. DAF-16/FOXO regulates transcription of cki-1/Cip/Kip and repression of lin-4 during C. elegans L1 arrest. Curr. Biol. 16, 780–785 (2006)

    CAS  Article  Google Scholar 

  7. Gems, D. et al. Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans. Genetics 150, 129–155 (1998)

    CAS  Article  Google Scholar 

  8. Kao, G. et al. ASNA-1 positively regulates insulin secretion in C. elegans and mammalian cells. Cell 128, 577–587 (2007)

    CAS  Article  Google Scholar 

  9. Olive, V., Jiang, I. & He, L. mir-17-92, a cluster of miRNAs in the midst of the cancer network. Int. J. Biochem. Cell Biol. 42, 1348–1354 (2010)

    CAS  Article  Google Scholar 

  10. Ibáñez-Ventoso, C., Vora, M. & Driscoll, M. Sequence relationships among C. elegans, D. melanogaster and human microRNAs highlight the extensive conservation of microRNAs in biology. PLoS ONE 3, e2818 (2008)

    ADS  Article  Google Scholar 

  11. Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009)

    CAS  Article  Google Scholar 

  12. Yi, R., Poy, M. N., Stoffel, M. & Fuchs, E. A skin microRNA promotes differentiation by repressing ‘stemness’. Nature 452, 225–229 (2008)

    ADS  CAS  Article  Google Scholar 

  13. 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)

    CAS  Article  Google Scholar 

  14. Reinhart, B. J. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901–906 (2000)

    ADS  CAS  Article  Google Scholar 

  15. Miska, E. A. et al. Most Caenorhabditis elegans microRNAs are individually not essential for development or viability. PLoS Genet. 3, 2395–2403 (2007)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  17. Meli, V. S., Osuna, B., Ruvkun, G. & Frand, A. R. MLT-10 defines a family of DUF644 and proline-rich repeat proteins involved in the molting cycle of Caenorhabditis elegans. Mol. Biol. Cell 21, 1648–1661 (2010)

    CAS  Article  Google Scholar 

  18. Monsalve, G. C., Van Buskirk, C. & Frand, A. R. LIN-42/PERIOD controls cyclical and developmental progression of C. elegans molts. Curr. Biol. 21, 2033–2045 (2011)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  20. Kimble, J. & Hirsh, D. The postembryonic cell lineages of the hermaphrodite and male gonads in Caenorhabditis elegans. Dev. Biol. 70, 396–417 (1979)

    CAS  Article  Google Scholar 

  21. Fukuyama, M. et al. C. elegans AMPKs promote survival and arrest germline development during nutrient stress. Biol. Open 1, 929–936 (2012)

    CAS  Article  Google Scholar 

  22. Furuyama, T. et al. Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem. J. 349, 629–634 (2000)

    CAS  Article  Google Scholar 

  23. Murphy, C. T. et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424, 277–283 (2003)

    ADS  CAS  Article  Google Scholar 

  24. Gissendanner, C. R., Crossgrove, K., Kraus, K. A., Maina, C. V. & Sluder, A. E. Expression and function of conserved nuclear receptor genes in Caenorhabditis elegans. Dev. Biol. 266, 399–416 (2004)

    CAS  Article  Google Scholar 

  25. Fuhrmann, G. et al. Mouse germline restriction of Oct4 expression by germ cell nuclear factor. Dev. Cell 1, 377–387 (2001)

    CAS  Article  Google Scholar 

  26. Akamatsu, W., DeVeale, B., Okano, H., Cooney, A. J. & van der Kooy, D. Suppression of Oct4 by germ cell nuclear factor restricts pluripotency and promotes neural stem cell development in the early neural lineage. J. Neurosci. 29, 2113–2124 (2009)

    CAS  Article  Google Scholar 

  27. Yilmaz, O. H. et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012)

    ADS  CAS  Article  Google Scholar 

  28. Lewis, J. A. & Fleming, J. T. Basic culture methods. Methods Cell Biol. 48, 3–29 (1995)

    CAS  Article  Google Scholar 

  29. Harfe, B. D. et al. Analysis of a Caenorhabditis elegans Twist homolog identifies conserved and divergent aspects of mesodermal patterning. Genes Dev. 12, 2623–2635 (1998)

    CAS  Article  Google Scholar 

Download references


We thank A. Fire, A. Frand, Y. Iino, S. Mitani, X. Wei and K. Shen for reagents and strains, and K. Iki for comments on the manuscript. Some C. elegans strains used in this study were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health National Center for Research Resources, and the MITANI Lab through the National Bio-Resource Project of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. This work was supported by Japan Society for the Promotion of Science KAKENHI grant numbers 23229001 (T.K.), 23370083 (K.K.), and MEXT KAKENHI grant numbers 24657081 (T.K.), 23116703 (M.F.).

Author information

Authors and Affiliations



H.K., M.F. and A.K. designed and performed the experiments; all authors analysed and interpreted the data; M.F., K.K. and T.K. supervised the project; H.K. and M.F. wrote the manuscript with comments from all authors.

Corresponding author

Correspondence to Masamitsu Fukuyama.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains a Supplementary Discussion, Supplementary Methods, Supplementary Figures 1-12 and Supplementary References. (PDF 2880 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kasuga, H., Fukuyama, M., Kitazawa, A. et al. The microRNA miR-235 couples blast-cell quiescence to the nutritional state. Nature 497, 503–506 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing