Preimplantation mouse embryo development involves temporal-spatial specification and segregation of three blastocyst cell lineages: trophectoderm, primitive endoderm and epiblast. Spatial separation of the outer-trophectoderm lineage from the two other inner-cell-mass (ICM) lineages starts with the 8- to 16-cell transition and concludes at the 32-cell stages. Accordingly, the ICM is derived from primary and secondary contributed cells; with debated relative EPI versus PrE potencies. We report generation of primary but not secondary ICM populations is highly dependent on temporal activation of mammalian target of Rapamycin (mTOR) during 8-cell stage M-phase entry, mediated via regulation of the 7-methylguanosine-cap (m7G-cap)-binding initiation complex (EIF4F) and linked to translation of mRNAs containing 5' UTR terminal oligopyrimidine (TOP-) sequence motifs, as knockdown of identified TOP-like motif transcripts impairs generation of primary ICM founders. However, mTOR inhibition-induced ICM cell number deficits in early blastocysts can be compensated by the late blastocyst stage, after inhibitor withdrawal; compensation likely initiated at the 32-cell stage when supernumerary outer cells exhibit molecular characteristics of inner cells. These data identify a novel mechanism specifically governing initial spatial segregation of mouse embryo blastomeres, that is distinct from those directing subsequent inner cell formation, contributing to germane segregation of late blastocyst lineages.

Central European Institute of Technology Masaryk University Kamenice 753 5 62500 Brno Czech Republic

Department of Genetics and Reproduction Central European Institute of Technology Veterinary Research Institute Hudcova 296 70 621 00 Brno Czech Republic

Laboratory of Biochemistry and Molecular Biology of Germ Cells Institute of Animal Physiology and Genetics Czech Academy of Sciences Rumburská 89 27721 Liběchov Czech Republic

Laboratory of Cell Division Control Institute of Animal Physiology and Genetics Czech Academy of Sciences Rumburská 89 27721 Liběchov Czech Republic

Laboratory of Early Mammalian Developmental Biology Department of Molecular Biology and Genetics Faculty of Science University of South Bohemia Branišovská 31 37005 České Budějovice Czech Republic

Laboratory of Functional Genomics and Proteomics National Centre for Biomolecular Research Faculty of Science Masaryk University Kamenice 753 5 62500 Brno Czech Republic

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