Totipotency continuity from zygote to early blastomeres: a model under revision

Abstract

The mammalian zygote is a totipotent cell that generates all the cells of a new organism through embryonic development. However, if one asks about the totipotency of blastomeres after one or two zygotic divisions, opinions differ. As it is impossible to determine the individual developmental potency of early blastomeres in an intact embryo, experiments of blastomere isolation were conducted in various species, showing that two-cell blastomeres could give rise to a new organism when sister cells were separated. A mainstream interpretation was that each of the sister mammalian blastomeres was equally totipotent. However, reevaluation of those experiments raised some doubts about the real prevalence of cases in which this interpretation could truly be validated. We compiled experiments that tested the individual developmental potency of early mammalian blastomeres in a cell-autonomous way (i.e. excluding nuclear transfer and chimera production). We then confronted the developmental abilities with reported molecular differences between sister blastomeres. The reevaluated observations were at odds with the mainstream view: A viable two-cell embryo can already include one non-totipotent blastomere. We were, thus, led to propose a revised model for totipotency continuity based on the construction of the zygote as a mosaic, which accounts for differential inheritance of totipotency-relevant components between sister blastomeres. This takes place with no preordained mechanisms that would ensure a reproducible partition. This model, which is compatible with the body of data on regulative properties of mammalian early embryos, aims at tempering the rigid interpretation that discounted maternal constraints on totipotency.Reproduction (2019) 158 R49-R65

Developmental capacity is unevenly distributed among single blastomeres of 2-cell and 4-cell stage mouse embryos

“…However, later studies that sought to obtain twin mice from one 2-cell embryo provided vague results. Monozygotic twins resulting from the development of two separated sister blastomeres are rarely born, indicating an unequal developmental potential of blastomeres of the 2-cell embryo 4 – 9 . This observation does not contradict the totipotency of the 2-cell mouse embryo blastomeres, but suggests uneven developmental potential of the cells emerging from the first cleavage division 8 , 9 , 54 , 55 .…”

“…Mammalian zygotes, for example, can differentiate into all types of embryonic cells and transient extraembryonic structures, such as the placenta and fetal membranes. Moreover, a single blastomere isolated from a 2-cell mouse embryo can also develop into a blastocyst and then into offspring 3 ; however, attempts to experimentally obtain monozygotic twins in this species have rarely been successful 4 – 9 . This observation does not contradict the totipotency of 2-cell stage mouse blastomeres, but rather supports the idea that sister blastomeres are not equally totipotent 8 , 9 .…”

“…Moreover, a single blastomere isolated from a 2-cell mouse embryo can also develop into a blastocyst and then into offspring 3 ; however, attempts to experimentally obtain monozygotic twins in this species have rarely been successful 4 – 9 . This observation does not contradict the totipotency of 2-cell stage mouse blastomeres, but rather supports the idea that sister blastomeres are not equally totipotent 8 , 9 . In the mouse, starting at the 4-cell stage, single isolated blastomeres are not able to produce a functional blastocyst, which is most likely due to the insufficient number of cells at the time of implantation 10 – 18 .…”

Building Pluripotency Identity in the Early Embryo and Derived Stem Cells

“…Rather, unequal segregation of the zygote cytoplasmic components [8] may influence totipotency continuity in the blastomere pairs. Difficulties in preserving blastomeres undamaged hampered the possibility to document reproductive totipotency in 4-and 8-cell mouse embryos (for a review, see [9]). Then, embryonic cells evolve towards pluripotency while the embryos undergo through cellular events that occur at specific time points after fertilization.…”

A Critical Role for The COP9 Signalosome Subunit 3 as A Gatekeeper of Genome Integrity in 2-Cell Mouse Embryos

“…non-homogeneous mRNA distribution in the oocyte and difference of mRNA level between 2-cell blastomeres 5 ) is not consistent with a first-time requirement of this gene at postimplantation, as inferred from the timing of death of Cops3 knock-out embryos 6 . Furthermore, the observed in situ distribution of the Cops3 mRNA 5 is reminiscent of developmental mosaicism, which is a controversial issue in mammals 7 . Cops3 encodes a subunit of the Constitutive Photomorphogenic 9 (COP9) signalosome complex, whose subunits operate together (as a holocomplex) or as monomers 8 , as regulators of a wide range of biological processes that are ubiquitous in cells of plants and animals.…”