Preimplantation Embryo Development Flashcards
(189 cards)
1
Q
A. Mitotic Cleavages
A
2
Q
- Pre-lmplantation Embryo Development
A
3
Q
The zygotic cleavage is a vertical division through the main axis of the egg from the animal (site of
A
4
Q
polar body extrusion) to vegetal pole. The cleavage furrow often transverses the area where pronuclei
A
5
Q
resided at the initiation of syngamy. The astral centrosome containing two centrioles splits and the
A
6
Q
two halves move to opposite poles of the bipolar mitotic spindle to establish the bipolarization
A
7
Q
required to control cell division (Figure 4). The chromosomes organize at the equator of the
A
8
Q
metaphase spindle
A
after which anaphase and telophase occur to complete the first mitotic
9
Q
division.
A
10
Q
NOTE: The polymerization of tubulin into microtubules is a temperature sensitive process that is
A
11
Q
destabilized at temperatures below 37°C. In the oocyte
A
this could induce chromosome detachment
12
Q
drift
A
and induced aneuploidy if not carefully controlled.
13
Q
Microtubule (MT) fibers
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14
Q
form the metaphase
A
15
Q
spindle.
A
16
Q
2.14
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17
Q
One of the two spindle poles.
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18
Q
Each centriole polarizes the
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19
Q
MT fibers to make a bipolar
A
20
Q
spindle.
A
21
Q
Chromosomes align at
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22
Q
the spindle equator.
A
23
Q
Figure 4: The first mitotic spindle prior to the first mitotic division
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24
Q
Resulting daughter cells are termed blastomeres
A
and this terminology is used for distinct embryonic
25
cels until the time of compaction (Figure 5). The first 3 to 4 embryonic cleavage divisions are mitotic
26
with blastomeres receiving a full set of chromosomes and subsequent reductions in cytoplasm. The
27
first mitotic cell division cycle is comparatively long (22-36 hours; Montag et al.
2007). The
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second cleavage takes place approximately 16 hours later and thereafter cell division occurs at about
29
12 hour intervals. Blastomere fate has been much debated in recent years as to whether this is
30
random or patterned by the combined effects of cleavage plane orientations and embryonic polarities.
31
The patterning theory proposes that the fate of individual blastomeres has been imposed by the 4-
32
cell stage before embryo polarization occurs. However
all theories regarding mammnalian embryo
33
development must remain consistent with the observation that blastomeres from a four-cell embryo
34
have the developmental latitude to form four healthy offspring. Blastomeres having such developmental
35
potential are termed totipotent. While genetically this is true for blastomeres from mammalian embryos
36
until cell differentiation
practically this is problematic due to the small volume of cytoplasm in
37
blastomeres from later stage embryos. Once blastomeres begin to differentiate
they are no longer
38
totipotent. During early embryogenesis
totipotency is gradually lost with embryo compaction
39
polarization
and diferentiation of distinct inner cell mass (ICM) and trophectoderm (TE) cell
40
populations. The TE cells will further differentiate into the trophoblast that is later responsible for
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implantation
while the ICM cells give rise to pluripotent epiblast (EPI) cells and extra-embryonic
42
primitive endoderm (PrE) cells (second lineage differentiation). As the transition from totipotency to
43
pluripotency during embryogenesis occurs gradually
a term has been introduced to characterize early
44
human blastomeres
prior to commitment to ICM and TE: plenipotency (Condiac
45
cells are described as balancing between totipotency and differentiation in a state that is under the
46
control of cyclin E1 in the human embryo (Krivega et al.
2015). Pluripotency refers to the capacity to
47
differentiate into derivatives of all three embryonic germ layers: endo-
meso- and ectoderm
48
germ cells. As development progresses
pluripotency is lost as the EPI is driven to differentiate into
49
2.15
50
A. Mitotic Cleavages
51
3. Pre-lmplantation Embryo Development
52
The zygotic cleavage is a vertical division through the main axis of the egg from the animal (site of
53
polar body extrusion) to vegetal pole. The cleavage furrow often transverses the area where pronuclei
54
resided at the initiation of syngamy. The astral centrosome containing two centrioles splits and the
55
two halves move to opposite poles of the bipolar mitotic spindle to establish the bipolarization
56
required to control cell division (Figure 4). The chromosomes organize at the equator of the
57
metaphase spindle
after which anaphase and telophase occur to complete the first mitotic
58
division.
59
NOTE: The polymerization of tubulin into microtubules is a temperature sensitive process that is
60
destabilized at temperatures below 37°C. In the oocyte
this could induce chromosome detachment
61
drift
and induced aneuploidy if not carefully controlled.
62
Microtubule (MT) fibers
63
form the metaphase
64
spindle.
65
2.14
66
One of the two spindle poles.
67
Each centriole polarizes the
68
MT fibers to make a bipolar
69
spindle.
70
Chromosomes align at
71
the spindle equator.
72
Figure 4: The first mitotic spindle prior to the first mitotic division
73
Resulting daughter cells are termed blastomeres
and this terminology is used for distinct embryonic
74
cels until the time of compaction (Figure 5). The first 3 to 4 embryonic cleavage divisions are mitotic
75
with blastomeres receiving a full set of chromosomes and subsequent reductions in cytoplasm. The
76
first mitotic cell division cycle is comparatively long (22-36 hours; Montag et al.
2007). The
77
second cleavage takes place approximately 16 hours later and thereafter cell division occurs at about
78
12 hour intervals. Blastomere fate has been much debated in recent years as to whether this is
79
random or patterned by the combined effects of cleavage plane orientations and embryonic polarities.
80
The patterning theory proposes that the fate of individual blastomeres has been imposed by the 4-
81
cell stage before embryo polarization occurs. However
all theories regarding mammnalian embryo
82
development must remain consistent with the observation that blastomeres from a four-cell embryo
83
have the developmental latitude to form four healthy offspring. Blastomeres having such developmental
84
potential are termed totipotent. While genetically this is true for blastomeres from mammalian embryos
85
until cell differentiation
practically this is problematic due to the small volume of cytoplasm in
86
blastomeres from later stage embryos. Once blastomeres begin to differentiate
they are no longer
87
totipotent. During early embryogenesis
totipotency is gradually lost with embryo compaction
88
polarization
and diferentiation of distinct inner cell mass (ICM) and trophectoderm (TE) cell
89
populations. The TE cells will further differentiate into the trophoblast that is later responsible for
90
implantation
while the ICM cells give rise to pluripotent epiblast (EPI) cells and extra-embryonic
91
primitive endoderm (PrE) cells (second lineage differentiation). As the transition from totipotency to
92
pluripotency during embryogenesis occurs gradually
a term has been introduced to characterize early
93
human blastomeres
prior to commitment to ICM and TE: plenipotency (Condiac
94
cells are described as balancing between totipotency and differentiation in a state that is under the
95
control of cyclin E1 in the human embryo (Krivega et al.
2015). Pluripotency refers to the capacity to
96
differentiate into derivatives of all three embryonic germ layers: endo-
meso- and ectoderm
97
germ cells. As development progresses
pluripotency is lost as the EPI is driven to differentiate into
98
2.15
99
specialized developmentally restricted fates triggered by several factors that include fibroblast growth
100
factor
bone morphogenic protein
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Timing of embryo development: Embryos with the highest implantation potential have undergone
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the first mitotic cleavage to 2 cells by 25 hours post insemination
have 4 cells on Day 2
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on Day 3 (Shoukir et al.
1997). Blastocoel formation and expansion should be evident on day 5 of
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development. Implantation of human blastocysts developing after 6
7
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reported but implantation rates decrease as time to blastocyst development increases (Shoukir et al.
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1998).
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Day 5:
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blastocyst
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UTERUS
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Day 3-4:
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morula
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B. Zygotic Genome Activation (ZGA)
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Day 2:
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8-cells
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Day 2:
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4cells
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FALLOPIAN
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TUBE
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OVARY
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Day 1:
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Fertilized Egg
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Figure 5: The fertilized egg and early embryo remain in the fallopian tube for around 4 days before
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moving into the uterus
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The fully-grown mammalian oocyte is a non-proliferating
differentiated cell capable of producing
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o0cyte-specific gene products that upon fertilization support the embryo during the first few cell
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divisions. The o0cyte therefore unique in its ability to revert from a differentiated state to an
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undifferentiated state and finally back to a differentiated state. This transformation involves
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reprogramming the pattern of gene expression in the early embryo. This reprogramming
or onset of
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transcription
within the zygote has been termed zygotic gene or genome activation or Embryonic
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Genome Activation (EGA). ZGA results in the replacement of maternal transcripts that were
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degraded during oocyte maturation and generation of embryo specific transcripts. To fully
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appreciate ZGA one must first step back and consider transcriptional events and stability occurring
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within the oocyte that will eventually influence ZGA and embryonic developmental competence. The
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increase in total RNA during the oocyte growth phase has been estimated to be approximately 300-
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fold
of which approximately 10%-15% is mRNA. Transcription continues in the fully-grown oocyte
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albeit at a diminished rate
and declines to practically undetectable levels around the time of meiosis
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resumption. The onset of meiotic maturation triggers degradation of maternal transcripts and almost
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none remain following ZGA. As much as 50% of mRNA accumulated during oocyte growth is either
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deadenylated and/or degraded during meiotic maturation. The remaining transcripts and their
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translated proteins collectively constitute the maternal products that are required after fertilization and
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to support the first steps of embryonic development until ZGA. Indeed
protein synthesis is required in
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mouse embryos for activation of most
if not all
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be controlled
in part
145
le o'
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factors (Wang and Latham
1997). Studies have demonstrated that maternal fe
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modifying developmental ability and gene expression in the zygote. While their
148
elucidated
the quality and quantity of maternally-derived factors may serve as dete.
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survival of the newly formed zygote.
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75/154 t
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C. Compaction and Blastocyst Formation
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-lmatt
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ZGA timing is species dependent: In non-human primate and human embryos
ZGA occurs at the 4
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to 8 cell stage (Braude et al
1988). In the mouse
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correlates well with the 2-cell block that has been observed in outbred strains when embryos are
156
cultured under certain conditions. This maternally-derived 2-cell block can be overcome by transfer of
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unknown cytoplasmic factors from embryos that are not susceptible to this developmental block. One
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conclusion is that under some suboptimal culture conditions
hypersensitive maternaly-derived
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cytoplasmic factors that regulate ZGA are compromised resulting in developmental arrest. This
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observation underines the importance of maternally-derived factors in the regulation of embryo
161
developmental competence. While the major ZGA in the mouse occurs at the 2-cell stage
some
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transcription is evident in the latter part of the first embryonic cell cycle and appears to take place
163
primarily in the male pronucleus. This event has been referred to as the minor ZGA. It should therefore
164
be considered that a step-wise activation of the zygotic genome may also occur in the human
165
embryo
and failure of the process may contribute to embryonic developmental arrest at the 4- to 8-
166
cell stage. Some maternally derived proteins persist beyond the stage of ZGA and are required at later
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stages for continued embryo development.
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Morula is the term used to describe an embryo with more than 8 blastomeres
and refers to its
169
resemblance to a mulberry (Figure 5). The compaction process involves maximizing intracellular
170
contacts and formation of tight junctions between adjacent blastomeres that lose their distinct
171
appearance and are no longer totipotent. Furthermore
the embryo becomes developmentally
172
polarized; cells within the inner portion of the morula maintain a radially symmetrical phenotype (non-
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polartzed) and ultimately develop into the inner cell mass (1CM)
whereas the outer cell layer of the
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morula become highly polarized and contribute to the trophectoderm (TE) or trophoblast cell
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population.
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The morula-to-blastocyst transition involves the formation of a fluid-filled cavity called a blastocoel.
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Fluid accumulates initially in cavities between adjacent cellis of the compacting morula. These isolated
178
pools of fluid then coalesce to form one large cavity. Fluid accumulation is brought about by solute
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gradients established by active ion transport involving sodium/potassium (Naʻ/K*) ATPase pumps and
180
the formation of tight junctional complexes between cells. As the blastocyst expands
the two cell layers
181
of the blastocyst (ICM and TE) become discernible. The TE is a single cell layer that surrounds the
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blastocoel
and will ultimately give rise to the chorion or fetal portion of the placenta. The ICM is
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suspended at one pole of the blastocoel and will ultimately give rise to the embryo proper and develop
184
into three primary embryonic germ layers: ectoderm
mesoderm
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been established as an essential basis for controlled gene action and tissue differentiation. The
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blastocyst is clearly polarized with the ICM located toward the embryonic pole
although when and how
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polarity is established and whether it is random or biased due to pre-pattern in the zygote are
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unresolved (Edwards
2006).
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