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mediating the developmental fate of each blastomere and distinction between the
four classes of four-cell mammalian embryos remains to be determined (Ajduk and
Zernicka-Goetz 2015 ).
In addition to unique cell orientation, the time between cleavage divisions in
mammalian embryos is more prolonged, typically between 8 and 24 h apart depend-
ing on the species, compared to that in many nonmammalian vertebrates. For
instance, the time between the first and second mitosis in mice is approximately 20
h and for the majority of other mammals, including humans, 8–12 h (O'Farrell et al.
2004 ; Wong et al. 2010 ; Weinerman et al. 2016 ). Besides longer time intervals, blas-
tomeres in early cleavage-stage mammalian embryos also undergo asynchronous
cell division rather than simultaneously dividing like in other vertebrates. Therefore,
mammalian preimplantation embryos do not increase exponentially in cell number
from the two- to four- or four- to eight-cell stage but can contain an odd number of
blastomeres at certain times in development (Gilbert 2000 ). Lastly, in contrast to
other vertebrate animals, the mammalian genome becomes activated much earlier,
and many of the mRNA transcripts and protein products produced from embryonic
genome activation (EGA) are required for subsequent cell divisions. Because of this
requirement, the stage of embryo development that coincides with EGA is most
susceptible to cleavage arrest or “block” in several mammalian species (Ko et al.
2000 ). The mouse embryo exhibits EGA earliest, at the two-cell stage; however,
minor transcription of certain mRNAs also occurs in mouse embryos at the one-cell
stage and is often referred to as zygotic gene activation (ZGA) (Flach et al. 1982 ;
Ko et al. 2000 ; Hamatani et al. 2004 ; Wang et al. 2004 ; Zeng et al. 2004 ). Similar to
the mouse, human embryos have also been shown to undergo minor transcriptional
activity of preferential mRNAs prior to the major wave of EGA, and some of the
transcripts include cell cycle regulators (Dobson et al. 2004 ; Zhang et al. 2009 ;
Galán et al. 2010 ; Vassena et al. 2011 ). Thus, it is likely that preimplantation
embryos from other mammalian species also exhibit “waves” of gene expression
during the transition from maternal to embryonic transcriptional control, which may
impact embryo behavior and cell division timing if these cell cycle-related genes are
aberrantly expressed. Regardless of which wave it occurs under, the production of
embryo-derived transcripts is clearly established by day 3 of human preimplanta-
tion development even in embryos that arrested prior to the eight-cell stage (Dobson
et al. 2004 ; Zhang et al. 2009 ; Galán et al. 2010 ; Vassena et al. 2011 ), suggesting
that EGA is a function of time rather than cell number per se.
Several studies have shown that male mammalian preimplantation embryos may
actually cleave faster than female embryos cultured in vitro (Xu et al. 1992 ;
Pergament et al. 1994 ; Peippo and Bredbacka 1995 ), although other studies detected
no difference in the sex ratios between early- or late-cleaving human embryos (Ng
et al. 1995 ; Lundin et al. 2001 ). This suggests that potential sex-related differences
in the cleavage rate of male versus female human embryos do not occur until later
during post-implantation development or that, alternatively, this phenomenon is
restricted to only certain mammalian species. Nevertheless, early cleavage in gen-
eral is a strong indicator of embryo viability since human embryos that undergo the
first mitotic division sooner appear to have greater potential for successful implanta-
A. Hasley et al.