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Myc-driven endogenous cell competition in the early mammalian embryo

Abstract

The epiblast is the mammalian embryonic tissue that contains the pluripotent stem cells that generate the whole embryo. We have established a method for inducing functional genetic mosaics in the mouse. Using this system, here we show that induction of a mosaic imbalance of Myc expression in the epiblast provokes the expansion of cells with higher Myc levels through the apoptotic elimination of cells with lower levels, without disrupting development. In contrast, homogeneous shifts in Myc levels did not affect epiblast cell viability, indicating that the observed competition results from comparison of relative Myc levels between epiblast cells. During normal development we found that Myc levels are intrinsically heterogeneous among epiblast cells, and that endogenous cell competition refines the epiblast cell population through the elimination of cells with low relative Myc levels. These results show that natural cell competition in the early mammalian embryo contributes to the selection of the epiblast cell pool.

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Figure 1: Myc overexpression promotes dose-dependent expansion of cell populations in mosaic embryos.
Figure 2: Expansion of Myc-overexpressing cells requires apoptosis of wild-type cells in the epiblast of early mosaic embryos.
Figure 3: Myc-induced cell competition is triggered by short-range interactions.
Figure 4: Epiblast cells with low Myc expression preferentially undergo natural apoptosis.
Figure 5: Cell death in ES cells correlates with low Myc levels and anabolic activity.
Figure 6: Endogenous cell competition in the mouse epiblast selects cells with higher relative Myc levels.

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Acknowledgements

We thank S. Srinivas for pBigT and pROSA26PA vectors; I. Moreno de Alborán for Mycflox/flox mice; C. G. Arques for suggestions and patience; M. Manzanares for comments on the manuscript; L. M. Criado and S. Ortega for mouse generation; T. Córdoba, V. García, E. Escudero and S. Vela for mouse work; J. L. Ligos, M. Vitón and R. Nieto for help with flow cytometry; E. Arza and A. M. Santos for help with microscopy and three-dimensional reconstruction; F. Sánchez-Cabo and P. López-Romero for statistics; and S. Bartlett for text editing. The CNIC is supported by the Ministerio de Economia y Competitividad (MINECO) and the Pro-CNIC Foundation. This work was supported by a MINECO/ISCIII TerCel grant (RD06/0010/0008) and the Human Frontiers Science Program (RGP0008/2004). C.C. is supported by grants from the Madrid Regional Government (S-SAL-0190-2006 and P2010/BMD-2315).

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Authors and Affiliations

Authors

Contributions

C.C. designed the iMOS system, assembled the DNA constructs and performed the experiments and image acquisition; G.G. electroporated ES cells and screened them; G.G., C.C. and M.T. derived iMOS ES cells; R.S. genotyped the mice and embryos and performed histological processing; C.C. and M.T. designed the experiments, quantified and analysed the data and wrote the paper.

Corresponding author

Correspondence to Miguel Torres.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data, Supplementary References and Supplementary Figures 1-22. (PDF 26215 kb)

Supplementary Data

This zipped file contains the Source Data files for Supplementary Figures 2, 6, 7, 8, 9, 10, 11, 12, 18, 19, 20 and 22. (ZIP 433 kb)

3-D animation of the distribution of Myc-overexpressing cells and apoptotic cells in the mouse epiblast

3D reconstruction from confocal sections of an E6.5 iMOST1-Myc; Sox2-Cre mosaic embryo showing DAPI-stained nuclei of WT cells (blue), Myc-overexpressing EYFP cells (green), and WT apoptotic cells stained for active Bax (magenta) and/or active Caspase-9 (red). (MP4 2416 kb)

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Clavería, C., Giovinazzo, G., Sierra, R. et al. Myc-driven endogenous cell competition in the early mammalian embryo. Nature 500, 39–44 (2013). https://doi.org/10.1038/nature12389

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