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In recent decades we have witnessed unprecedented progress in the field of the developmental biology of mammals. Building on 20th century discoveries, we have managed to increase our understanding of the molecular and cellular mechanisms governing early mammalian embryogenesis and link them to other biological questions, such as stem cells, regeneration, cancer, or tissue and organ formation. Consequently, it has also led to a creation of a completely new branch of reproductive medicine, i.e. assisted reproductive technology (ART). In this Special Issue of The International Journal of Developmental Biology (Int. J. Dev. Biol.) we wished to review state-ofthe- art research regarding early mammalian development, from fertilization up to the implantation stage, and discuss its potential meaning for practical applications, including ART. As an introduction to the issue we present a compilation of short essays written by the most renowned scientists in the field, working both in basic and clinical research. The essays are dedicated to the greatest breakthroughs and challenges of 21st century developmental biology and reproductive medicine. [ABSTRACT FROM AUTHOR]

During preimplantation mouse development stages, emerging pluripotent epiblast (Epi) and extraembryonic primitive endoderm (PrE) cells are first distributed in the blastocyst in a “salt-and-pepper” manner before they segregate into separate layers. As a result of segregation, PrE cells become localised on the surface of the inner cell mass (ICM), and the Epi is enclosed by the PrE on one side and by the trophectoderm on the other. During later development, a subpopulation of PrE cells migrates away from the ICM and forms the parietal endoderm (PE), while cells remaining in contact with the Epi form the visceral endoderm (VE). Here, we asked: what are the mechanisms mediating Epi and PrE cell segregation and the subsequent VE vs PE specification? Differences in cell adhesion have been proposed; however, we demonstrate that the levels of plasma membrane-bound E-cadherin (CDH1, cadherin 1) in Epi and PrE cells only differ after the segregation of these lineages within the ICM. Moreover, manipulating E-cadherin levels did not affect lineage specification or segregation, thus failing to confirm its role during these processes. Rather, we report changes in E-cadherin localisation during later PrE-to-PE transition which are accompanied by the presence of Vimentin and Twist, supporting the hypothesis that an epithelial-to-mesenchymal transition process occurs in the mouse peri-implantation blastocyst. [ABSTRACT FROM AUTHOR]

Formation of epiblast (EPI) - the founder line of all embryonic lineages - and extra-embryonic supportive tissues is one of the key events in mammalian development. The prevailing model of early mammalian development is based almost exclusively on the mouse. Here, we provide a comprehensive, stage-by-stage analysis of EPI and extra-embryonic primitive endoderm (PrE) formation during preimplantation development of the rabbit. Although we observed that rabbit embryos have several features in common with mouse embryos, including a stage-related initiation of lineage specification, our results demonstrate the existence of some key differences in lineage specification among mammals. Contrary to the current view, our data suggest that reciprocal repression of GATA6 and NANOG is not fundamental for the initial stages of PrE versus EPI specification in mammals. Furthermore, our results provide insight into the observed discrepancies relating to the role of FGF/ERK signalling in PrE versus EPI specification between mouse and other mammals. [ABSTRACT FROM AUTHOR]

Embryonic development is a complex and highly dynamic process during which individual cells interact with one another, adopt different identities and organize themselves in three-dimensional space to generate an entire organism. Recent technical developments in genomics and high-resolution quantitative imaging are making it possible to study cellular populations at single-cell resolution and begin to integrate different inputs, for example genetic, physical and chemical factors, that affect cell differentiation over spatial and temporal scales. The preimplantation mouse embryo allows the analysis of cell fate decisions in vivo with high spatiotemporal resolution. In this review we highlight how the application of live imaging and single-cell resolution analysis pipelines is providing an unprecedented level of insight on the processes that shape the earliest stages of mammalian development. [ABSTRACT FROM AUTHOR]

One of the unanswered questions in mammalian development is how the embryonic-abembryonic axis of the blastocyst is first established. It is possible that the first cleavage division contributes to this process, because in most mouse embryos the progeny of one two-cell blastomere primarily populate the embryonic part of the blastocyst and the progeny of its sister populate the abembryonic part. However, it is not known whether the embryonic-abembryonic axis is set up by the first cleavage itself, by polarity in the oocyte that then sets the first cleavage plane with respect to the animal pole, or indeed whether it can be divorced entirely from the first cleavage and established in relation to the animal pole. Here we test the importance of the orientation of the first cleavage by imposing an elongated shape on the zygote so that the division no longer passes close to the animal pole, marked by the second polar body. Non-invasive lineage tracing shows that even when the first cleavage occurs along the short axis imposed by this experimental treatment, the progeny of the resulting two-cell blastomeres tend to populate the respective embryonic and abembryonic parts of the blastocyst. Thus, the first cleavage contributes to breaking the symmetry of the embryo, generating blastomeres with different developmental characteristics. [ABSTRACT FROM AUTHOR]

The conservation of early cleavage patterns in organisms as diverse as echinoderms and mammals suggests that even in highly regulative embryos such as the mouse, division patterns might be important for development. Indeed, the first cleavage divides the fertilized mouse egg into two cells: one cell that contributes predominantly to the embryonic part of the blastocyst, and one that contributes to the abembryonic part. The zygotes of organisms as diverse as echinoderms and mammals follow stereotyped patterns of early cleavage division. This conservation suggests that, even in highly regulative embryos such as the mouse, division patterns are important in development. Here we show, by removing, transplanting or duplicating the animal or vegetal poles of the mouse egg, that a spatial cue at the animal pole orients the plane of this initial division. Embryos with duplicated animal, but not vegetal, poles show abnormalities in chromosome segregation that compromise their development. Our results show that localized factors in the mammalian egg orient the spindle and so define the initial cleavage plane. In increased dosage, however, these factors are detrimental to the correct execution of division. [ABSTRACT FROM AUTHOR]

Hiiragi et al. compare our model of the developing mouse egg with theirs. They seem to present patterning as equivalent to determination, but this is confusing as patterning does not have to mean determination. We have never stated that mouse embryo development is determined. Mouse development is regulative rather than determinative, and this can be explained in two ways: first, development could be entirely unbiased, generating identical cells; second, there could be some developmental bias or, in other words, pattern from the beginning that is not constraining. There is evidence for early bias from several laboratories but this does not mean that cells have localized determinants fixing their fates. Regulative development does not exclude bias, which indicates inclination, not determination. [ABSTRACT FROM AUTHOR]