Skip to main content

Thank you for visiting nature.com. 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.

c-Myc regulates mammalian body size by controlling cell number but not cell size

Abstract

Overexpression of the proto-oncogene c-myc has been implicated in the genesis of diverse human tumours. c-Myc seems to regulate diverse biological processes, but its role in tumorigenesis and normal physiology remains enigmatic1. Here we report the generation of an allelic series of mice in which c-myc expression is incrementally reduced to zero. Fibroblasts from these mice show reduced proliferation and after complete loss of c-Myc function they exit the cell cycle. We show that Myc activity is not needed for cellular growth but does determine the percentage of activated T cells that re-enter the cell cycle. In vivo, reduction of c-Myc levels results in reduced body mass owing to multiorgan hypoplasia, in contrast to Drosophila dmyc mutants, which are smaller as a result of hypotrophy2. We find that dmyc substitutes for c-myc in fibroblasts, indicating they have similar biological activities. This suggests there may be fundamental differences in the mechanisms by which mammals and insects control body size. We propose that in mammals c-Myc controls the decision to divide or not to divide and thereby functions as a crucial mediator of signals that determine organ and body size.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Generation of mutant c-myc alleles and analysis of mutant embryos.
Figure 2: Effect of altering c-myc expression on body and organ size.
Figure 3: Effect of altering c-myc expression on cell proliferation and morphology in primary and immortalized fibroblasts.
Figure 4: Activation, growth and proliferation potential of c-myc mutant naive CD4+ T cells.
Figure 5: Proliferation potential of c-mycΔORF/+ T cells in the absence of p27.

References

  1. 1

    Grandori, C., Cowley, S. M., James, L. P. & Eisenman, R. N. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu. Rev. Cell Dev. Biol. 16, 653–699 (2000).

    CAS  Article  Google Scholar 

  2. 2

    Johnston, L. A., Prober, D. A., Edgar, B. A., Eisenman, R. N. & Gallant, P. Drosophila myc regulates cellular growth during development. Cell 98, 779–790 (1999).

    CAS  Article  Google Scholar 

  3. 3

    Davis, A. C., Wims, M., Spotts, G. D., Hann, S. R. & Bradley, A. A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. Genes Dev. 7, 671–682 (1993).

    CAS  Article  Google Scholar 

  4. 4

    Orkin, S. H. & Zon, L. I. Genetics of erythropoiesis: induced mutations in mice and zebrafish. Annu. Rev. Genet. 31, 33–60 (1997).

    CAS  Article  Google Scholar 

  5. 5

    Van Parijs, L., Refaeli, Y., Abbas, A. K. & Baltimore, D. Autoimmunity as a consequence of retrovirus-mediated expression of C-FLIP in lymphocytes. Immunity 11, 763–770 (1999).

    CAS  Article  Google Scholar 

  6. 6

    de Alboran, I. M. et al. Analysis of c-myc function in normal cells via conditional gene-targeted mutation. Immunity 14, 45–55 (2001).

    CAS  Article  Google Scholar 

  7. 7

    Todaro, G. J. & Green, H. Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J. Cell Biol. 17, 299–313 (1963).

    CAS  Article  Google Scholar 

  8. 8

    Gallant, P., Shilo, Y., Cheng, P. F., Parkhurst, S. M. & Eisenman, R. N. Myc and Max homologs in Drosophila. Science 274, 1523–1527 (1996).

    ADS  CAS  Article  Google Scholar 

  9. 9

    Crabtree, G. R. Contingent genetic regulatory events in T lymphocyte activation. Science 243, 355–361 (1989).

    ADS  CAS  Article  Google Scholar 

  10. 10

    Kuhn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995).

    ADS  CAS  Article  Google Scholar 

  11. 11

    Radtke, F. et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10, 547–558 (1999).

    CAS  Article  Google Scholar 

  12. 12

    Vlach, J., Hennecke, S., Alevizopoulos, K., Conti, D. & Amati, B. Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc. EMBO J. 15, 6595–6604 (1996).

    CAS  Article  Google Scholar 

  13. 13

    O'Hagan, R. C. et al. Myc-enhanced expression of cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression. Genes Dev. 14, 2185–2191 (2000).

    CAS  Article  Google Scholar 

  14. 14

    Fero, M. L. et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficient mice. Cell 85, 733–744 (1996).

    CAS  Article  Google Scholar 

  15. 15

    Mateyak, M. K., Obaya, A. J., Adachi, S. & Sedivy, J. M. Phenotypes of c-Myc-deficient rat fibroblasts isolated by targeted homologous recombination. Cell Growth Differ. 8, 1039–1048 (1997).

    CAS  PubMed  Google Scholar 

  16. 16

    Eilers, M., Schirm, S. & Bishop, J. M. The myc protein activates transcription of the α-prothymosin gene. EMBO J. 10, 133–141 (1991).

    CAS  Article  Google Scholar 

  17. 17

    Blackwood, E. M., Kretzner, L. & Eisenman, R. N. Myc and Max function as a nucleoprotein complex. Curr. Opin. Genet. Dev. 2, 227–235 (1992).

    CAS  Article  Google Scholar 

  18. 18

    Schreiber-Agus, N. et al. Drosophila Myc is oncogenic in mammalian cells and plays a role in the diminutive phenotype. Proc. Natl Acad. Sci. USA 94, 1235–1240 (1997).

    ADS  CAS  Article  Google Scholar 

  19. 19

    Stevenson, R. D., Hill, M. F. & Bryant, P. J. Organ and cell allometry in Hawaiian Drosophila: how to make a big fly. Proc. R. Soc. Lond. B 259, 105–110 (1995).

    ADS  CAS  Article  Google Scholar 

  20. 20

    Conlon, I. & Raff, M. Size control in animal development. Cell 96, 235–244 (1999).

    CAS  Article  Google Scholar 

  21. 21

    Potter, C. J. & Xu, T. Mechanisms of size control. Curr. Opin. Genet. Dev. 11, 279–286 (2001).

    CAS  Article  Google Scholar 

  22. 22

    Stocker, H. & Hafen, E. Genetic control of cell size. Curr. Opin. Genet. Dev. 10, 529–535 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Selfridge, J., Pow, A. M., McWhir, J., Magin, T. M. & Melton, D. W. Gene targeting using a mouse HPRT minigene/HPRT-deficient embryonic stem cell system: inactivation of the mouse ERCC-1 gene. Somat. Cell Mol. Genet. 18, 325–336 (1992).

    CAS  Article  Google Scholar 

  24. 24

    Shivdasani, R. A., Mayer, E. L. & Orkin, S. H. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature 373, 432–434 (1995).

    ADS  CAS  Article  Google Scholar 

  25. 25

    Trumpp, A., Blundell, P. A., de la Pompa, J. L. & Zeller, R. The chicken limb deformity gene encodes nuclear proteins expressed in specific cell types during morphogenesis. Genes Dev. 6, 14–28 (1992).

    CAS  Article  Google Scholar 

  26. 26

    Refaeli, Y., Van Parijs, L., London, C. A., Tschopp, J. & Abbas, A. K. Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity 8, 615–623 (1998).

    CAS  Article  Google Scholar 

  27. 27

    Hölzel, M., Kohlgruber, F., Schlosser, I., Hölzel, D., Lüscher, B. & Eick, E. Myc/Max/Mad regulate the frequency but not the duration of productive cell cycles. EMBO Rep., 21 November 2001 (10.1093/embo-reports/kve251).

Download references

Acknowledgements

We thank J. Roberts and M. Fero for providing the p27KIP1 mice, S. Dymecki for the β-actin-FLP mice, D. Melton for HM1 ES cells, P. Gallant for dmyc cDNA, and L. VanParijs for pMIG-Cre. We thank G. Yee for performing the RNase protection analysis, S. Kogan for help with the methylcellulose cultures, D. Ginzinger for help with the initial Taqman analysis and C. McArthur, P. Zaech and A. Wilson for FACS sorting. We thank A. C. Pasche and D. Trail for technical assistance. We also thank M. Nabholz, S. Martin and our colleagues in the Trumpp, Bishop and Martin laboratories for discussions and critical reading of the manuscript. A.T. was the recipient of postdoctoral fellowships from the Deutsche Forschungsgemeinschaft, the Human Frontiers in Science Program, and the California Division of the American Cancer Society. A.T. is now supported by grants from the Swiss National Science Foundation and the Swiss Cancer League. Y.R. is a Merck fellow of the Life Sciences Research Foundation. This work was supported by the NIH (G.R.M. and J.M.B.), and the G.W. Hooper Foundation.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Andreas Trumpp.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Trumpp, A., Refaeli, Y., Oskarsson, T. et al. c-Myc regulates mammalian body size by controlling cell number but not cell size. Nature 414, 768–773 (2001). https://doi.org/10.1038/414768a

Download citation

Further reading

Comments

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.

Search

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