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.
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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.
The authors declare no competing financial interests.
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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
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