Samantha A. Morris a,b, Roy T. Y. Teo a,b,c, Huiliang Li e, Paul Robson c,d, David M. Glover f, and
Magdalena Zernicka-Goetz a,b,1
-Author Affiliations
aWellcome Trust/Cancer Research UK Gurdon Institute,
bDepartment of Physiology, Development and Neuroscience, and
fDepartment of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom;
cStem Cell and Developmental Biology, Genome Institute of Singapore, Republic of Singapore 138672;
dDepartment of Biological Sciences, National University of Singapore, Republic of Singapore 117543; and
eWolfson Institute for Biomedical Research and Department of Biology, University College London, London WC1E 6BT, Unitd Kingdom
Edited* by John B. Gurdon, University of Cambridge, Cambridge, United Kingdom, and approved February 25, 2010 (received for review December 28, 2009)
Abstract
A crucial question in mammalian development is how cells of the early embryo differentiate into distinct cell types. The first decision is taken when cells undertake waves of asymmetric division that generate one daughter on the inside and one on the outside of the embryo. After this division, some cells on the inside remain pluripotent and give rise to the epiblast, and hence the future body, whereas others develop into the primitive endoderm, an extraembryonic tissue. How the fate of these inside cells is decided is unknown: Is the process random, or is it related to their developmental origins? To address this question, we traced all cells by live-cell imaging in intact, unmanipulated embryos until the epiblast and primitive endoderm became distinct. This analysis revealed that inner cell mass (ICM) cells have unrestricted developmental potential. However, cells internalized by the first wave of asymmetric divisions are biased toward forming pluripotent epiblast, whereas cells internalized in the next two waves of divisions are strongly biased toward forming primitive endoderm. Moreover, we show that cells internalized by the second wave up-regulate expression of Gata6 and Sox17, and changing the expression of these genes determines whether the cells become primitive endoderm. Finally, with our ability to determine the origin of cells, we find that inside cells that are mispositioned when they are born can sort into the correct layer. In conclusion, we propose a model in which the timing of cell internalization, cell position, and cell sorting combine to determine distinct lineages of the preimplantation mouse embryo.
cell fate epiblast primitive endoderm Gata6 Sox17
Footnotes
1To whom correspondence should be addressed. E-mail:mzg@mole.cam.ac.uk.
Author contributions: M.Z.-G., S.A.M., and P.R. designed research; S.A.M. and R.T.Y.T. performed research; H.L. contributed new reagents/analytic tools; S.A.M., D.M.G., and M.Z.-G. analyzed data; and M.Z.-G., D.M.G., and S.A.M. wrote the paper.
The authors declare no conflict of interest.
↵*This Direct Submission article had a prearranged editor.
This article contains supplementary information online at www.pnas.org/cgi/content/full/0915063107/DCSupplemental.
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