Abstract
Following fertilization in mammals, it is generally accepted that totipotent cells are exclusive to the zygote and to each of the two blastomeres originating from the first mitotic division. This model of totipotency was inferred from a minority of cases in which blastomeres produced monozygotic twins in mice. Was this due to experimental limitation or biological constraint? Here we removed experimental obstacles and achieved reliable quantification of the prevalence of dual totipotency among mouse two-cell stage blastomeres. We separated the blastomeres of 1,252 two-cell embryos, preserving 1,210 of the pairs. Two classes of monozygotic twins became apparent at the blastocyst stage: 27% formed a functional epiblast in both members (concordant), and 73% did so in only one member of the pair (discordant) – a partition that proved insensitive to oocyte quality, sperm-entry point, culture environment and pattern of cleavage. In intact two-cell embryos, the ability of sister blastomeres to generate epiblast was also skewed. Class discovery clustering of the individual blastomeres’ and blastocysts’ transcriptomes points to an innate origin of concordance and discordance rather than developmental acquisition. Our data place constraints on the commonly accepted idea that totipotency is allocated equally between the two-cell stage blastomeres in mice.
Highlights
One of the key goals in developmental and reproductive biology is to better understand totipotency: the capability of a single cell to produce a fertile adult organism when placed in a supportive environment[1, 2]
A reconsideration of totipotency may allow the reconciliation of the different views on the biology of the first two blastomeres: The view that the sister blastomeres are inherently the same, and the view that the sister blastomeres are inherently different[19]
It is generally accepted that the totipotent cells of the mammalian life cycle are the zygote and each of the two blastomeres originating from the first mitotic division of the zygote
Summary
One of the key goals in developmental and reproductive biology is to better understand totipotency: the capability of a single cell to produce a fertile adult organism when placed in a supportive environment[1, 2]. There have been more mice produced by the more invasive and difficult method of somatic cell nuclear transfer (SCNT) than by the simpler method of two-cell embryo bisection Given these records, it is almost inevitable that the question as to whether the two sister blastomeres are totipotent has remained open. Our data place constraints on the commonly accepted idea that totipotency is allocated between the two-cell-stage blastomeres in mice based on 1) a minimally detrimental manipulation of 1,252 two-cell embryos, and 2) multiple endpoints including the gene expression of sister blastomeres and the germ layer makeup of the resultant MZ blastocysts (EPI, TE, pEnd). A reconsideration of totipotency may allow the reconciliation of the different views on the biology of the first two blastomeres: The view that the sister blastomeres are inherently the same (failures to produce two mice are due to experimental damage to one blastomere, for example), and the view that the sister blastomeres are inherently different (failures to produce two mice are due to this difference)[19]
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