During mouse preimplantation embryo development, three distinct cell lineages are formed, represented by the differentiating trophectoderm (TE), primitive endoderm (PrE) and the pluripotent epiblast (EPI). Classically, lineage derivation has been presented as a two-step process whereby outer TE cells are first segregated from inner-cell mass (ICM), followed by ICM refinement into either the PrE or EPI. As ICM founders can be produced following the fourth or fifth cleavage divisions, their potential to equally contribute to EPI and PrE is contested. Thus, modelling the early sequestration of ICM founders from TE-differentiation after the fourth cleavage division, we examined ICM lineage contribution of varying sized cell clones unable to initiate TE-differentiation. Such TE-inhibited ICM cells do not equally contribute to EPI and PrE and are significantly biased to form EPI. This bias is not caused by enhanced expression of the EPI marker Nanog, nor correlated with reduced apical polarity but associated with reduced expression of PrE-related gene transcripts (Dab2 and Lrp2) and down-regulation of plasma membrane associated Fgfr2. Our results favour a unifying model were the three cell lineages are guided in an integrated, yet flexible, fate decision centred on relative exposure of founder cells to TE-differentiative cues.

Institute of Entomology Biology Centre of the Czech Academy of Sciences Branišovská 31 37005 České Budějovice CZECH REPUBLIC

Laboratory of Developmental Biology and Genetics Department of Molecular Biology Faculty of Science University of South Bohemia Branišovská 31 37005 České Budějovice CZECH REPUBLIC

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Rossant J. & Tam P. P. Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse. Development 136, 701–713, 10.1242/dev.017178 (2009). PubMed DOI

Zernicka-Goetz M., Morris S. A. & Bruce A. W. Making a firm decision: multifaceted regulation of cell fate in the early mouse embryo. Nat Rev Genet 10, 467–477 (2009). PubMed

Schrode N. PubMed DOI PMC

Johnson M. H. & Ziomek C. A. The foundation of two distinct cell lineages within the mouse morula. Cell 24, 71–80 (1981). PubMed

Sutherland A. E., Speed T. P. & Calarco P. G. Inner cell allocation in the mouse morula: the role of oriented division during fourth cleavage. Dev Biol 137, 13–25 (1990). PubMed

Anani S., Bhat S., Honma-Yamanaka N., Krawchuk D. & Yamanaka Y. Initiation of Hippo signaling is linked to polarity rather than to cell position in the pre-implantation mouse embryo. Development 141, 2813–2824, 10.1242/dev.107276 (2014). PubMed DOI

Johnson M. H. From mouse egg to mouse embryo: polarities, axes, and tissues. Annu Rev Cell Dev Biol 25, 483–512 (2009). PubMed

Yagi R. PubMed

Nishioka N. PubMed

Strumpf D. PubMed

Mitsui K. PubMed

Morrisey E. E. PubMed PMC

Koutsourakis M., Langeveld A., Patient, R., Beddington, R. & Grosveld, F. The transcription factor GATA6 is essential for early extraembryonic development. Development 126, 723–732 (1999). PubMed

Cai K. Q., Capo-Chichi C. D., Rula M. E., Yang D. H. & Xu X. X. Dynamic GATA6 expression in primitive endoderm formation and maturation in early mouse embryogenesis. Dev Dyn 237, 2820–2829, 10.1002/dvdy.21703 (2008). PubMed DOI PMC

Niakan K. K. PubMed DOI PMC

Nishioka N. PubMed DOI

Hirate Y. PubMed DOI PMC

Cockburn K., Biechele S., Garner J. & Rossant J. The Hippo pathway member Nf2 is required for inner cell mass specification. Curr Biol 23, 1195–1201, 10.1016/j.cub.2013.05.044 (2013). PubMed DOI

Leung C. Y. & Zernicka-Goetz M. Angiomotin prevents pluripotent lineage differentiation in mouse embryos via Hippo pathway-dependent and -independent mechanisms. Nat Commun 4, 2251, 10.1038/ncomms3251 (2013). PubMed DOI PMC

Nichols J., Silva J., Roode M. & Smith A. Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development 136, 3215–3222 (2009). PubMed PMC

Frankenberg S. PubMed DOI

Morris S. A. PubMed DOI PMC

Morris S. A. & Zernicka-Goetz M. Formation of distinct cell types in the mouse blastocyst. Results and problems in cell differentiation 55, 203–217, 10.1007/978-3-642-30406-4_11 (2012). PubMed DOI

Yamanaka Y., Lanner F. & Rossant J. FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst. Development 137, 715–724, 10.1242/dev.043471 (2010). PubMed DOI

Morris S. A. Cell fate in the early mouse embryo: sorting out the influence of developmental history on lineage choice. Reprod Biomed Online 22, 521–524, 10.1016/j.rbmo.2011.02.009 (2011). PubMed DOI

Krupa M. PubMed DOI

Ziomek C. A. & Johnson M. H. Cell surface interaction induces polarization of mouse 8-cell blastomeres at compaction. Cell 21, 935–942 (1980). PubMed

Plusa B. PubMed

Skamagki M., Wicher K. B., Jedrusik A., Ganguly S. & Zernicka-Goetz M. Asymmetric localization of Cdx2 mRNA during the first cell-fate decision in early mouse development. Cell Rep 3, 442–457, 10.1016/j.celrep.2013.01.006 (2013). PubMed DOI PMC

Bruce A. W. & Zernicka-Goetz M. Developmental control of the early mammalian embryo: competition among heterogeneous cells that biases cell fate. Curr Opin Genet Dev 20, 485–491, 0.1016/j.gde.2010.05.006 (2010). PubMed

Morris S. A., Graham S. J., Jedrusik A. & Zernicka-Goetz M. The differential response to Fgf signalling in cells internalized at different times influences lineage segregation in preimplantation mouse embryos. Open Biol 3, 130104, 10.1098/rsob.130104 (2013). PubMed DOI PMC

Artus J., Babinet C. & Cohen-Tannoudji M. The cell cycle of early mammalian embryos: lessons from genetic mouse models. Cell cycle 5, 499–502 (2006). PubMed

Home P. PubMed PMC

Ralston A. PubMed DOI

Plusa B., Piliszek A., Frankenberg S., Artus J. & Hadjantonakis A. K. Distinct sequential cell behaviours direct primitive endoderm formation in the mouse blastocyst. Development 135, 3081–3091 (2008). PubMed PMC

Gardner R. L. & Rossant J. Investigation of the fate of 4-5 day post-coitum mouse inner cell mass cells by blastocyst injection. J Embryol Exp Morphol 52, 141–152 (1979). PubMed

Chazaud C., Yamanaka Y., Pawson T. & Rossant J. Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Dev Cell 10, 615–624 (2006). PubMed

Gerbe F., Cox B., Rossant J. & Chazaud C. Dynamic expression of Lrp2 pathway members reveals progressive epithelial differentiation of primitive endoderm in mouse blastocyst. Dev Biol 313, 594–602, 10.1016/j.ydbio.2007.10.048 (2008). PubMed DOI

Yang D. H., Cai K. Q., Roland I. H., Smith E. R. & Xu X. X. Disabled-2 is an epithelial surface positioning gene. J Biol Chem 282, 13114–13122, 10.1074/jbc.M611356200 (2007). PubMed DOI

Home P. PubMed DOI PMC

Salas-Vidal E. & Lomeli H. Imaging filopodia dynamics in the mouse blastocyst. Dev Biol 265, 75–89 (2004). PubMed

Bagheri-Fam S. PubMed DOI

Martin A. J. PubMed DOI PMC

Wicklow E. PubMed DOI PMC

Bessonnard S. PubMed DOI

Ohnishi Y. PubMed DOI PMC

Bruce A. W. Generating different genetic expression patterns in the early embryo: insights from the mouse model. Reprod Biomed Online 27, 586–592, 10.1016/j.rbmo.2013.03.024 (2013). PubMed DOI

Boroviak T., Loos R., Bertone P., Smith A. & Nichols J. The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification. Nat Cell Biol 16, 516–528, 10.1038/ncb2965 (2014). PubMed DOI PMC

Zhao B., Li L., Tumaneng K., Wang C. Y. & Guan K. L. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev 24, 72–85, 10.1101/gad.1843810 (2010). PubMed DOI PMC

Zernicka-Goetz M. PubMed

Livak K. J. & Schmittgen T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402–408 (2001). PubMed

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