143tion and positive pregnancy outcome (Lundin et al. 2001 ). More recent findings,
however, suggest that it is the duration of the first cleavage division rather than its
onset, together with the time intervals between the first three mitotic divisions, that
is highly predictive of which human embryos will reach the blastocyst stage (Wong
et al. 2010 ). Since this initial report, other studies have confirmed the importance of
early cleavage divisions and identified additional cell cycle or morphological
parameters predictive of developmental success (Cruz et al. 2011 , 2012 ; Meseguer
et al. 2011 , 2012 ; Azzarello et al. 2012 ; Dal Canto et al. 2012 ; Hashimoto et al.
2012 ; Hlinka et al. 2012 ; Rubio et al. 2012 ; Liu et al. 2014 , 2015 ; Stensen et al.
2015 ) as well as underlying chromosomal composition (Chavez et al. 2012 , 2014 ;
Campbell et al. 2013 ; Basile et al. 2014 ; Yang et al. 2014 ). Whether the first three
mitotic divisions are similarly predictive of embryo viability and/or chromosomal
status for other mammalian species is still under investigation, but an examination
of early mitotic timing in murine, bovine, and rhesus monkeys has suggested that
this is likely the case (Pribenszky et al. 2010 ; Sugimura et al. 2012 ; Burruel et al.
2014 ). As mentioned above, however, the precise timing between the first cell divi-
sions can vary between different mammalian species (O'Farrell et al. 2004 ; Wong
et al. 2010 ; Weinerman et al. 2016 ), and the underlying cause(s) remains largely
unknown. Besides a later EGA onset in comparison to the mouse, human embryos
have also been shown to express diminished levels of cell cycle checkpoints and
robust expression of cell cycle drivers at the cleavage stage (Harrison et al. 2000 ;
Los et al. 2004 ). This can impact not only embryo chromosomal stability, as shown
by the high incidence of whole chromosomal abnormalities (aneuploidy) in
cleavage- stage human embryos (Vanneste et al. 2009 ; Johnson et al. 2010 ; Chavez
et al. 2012 ; Chow et al. 2014 ), but may also produce preimplantation embryos that
cleave at a faster rate over other mammals. Moreover, time-lapse monitoring of
early embryonic development has demonstrated that human embryos also fre-
quently undergo multipolar divisions, whereby zygotes or blastomeres divide into
three or more daughter cells rather than the typical two. Indeed, it has been esti-
mated that approximately 12 % of human zygotes cultured in vitro are characterized
by multipolar divisions (Chamayou et al. 2013 ), and this phenomenon could further
explain differences in mitotic timing between mammalian species. While the poten-
tial impact of higher-order divisions at the two-cell stage and beyond may not be as
detrimental and is still being investigated, embryos that exhibit multipolar divisions
at the zygote stage are much less likely to form blastocysts and implant than zygotes
that undergo a bipolar division (Hlinka et al. 2012 ).
4.3.4.3 Proto-vertebrates
Studies in ascidians have provided important insights into patterns of cell cleavage
in a lineage basal to vertebrates, which may reflect ancestral developmental mecha-
nisms. Cleavage pattern in ascidian species is holoblastic, invariant, and character-
ized by bilateral symmetry (Conklin 1905 ; Nishida and Satoh 1983 ; Nishida 1987 ).
The pattern of cell cleavage orientation in ascidians provides insights into our
4 Vertebrate Embryonic Cleavage Pattern Determination