Difference between revisions of "Blastocyst Development"

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Human Blastocyst (day 5)[1]

(Greek, blastos = sprout + cystos = cavity) or blastula, the term used to describe the hollow cellular mass that forms in early development.

The blastocyst consists of cells forming an outer trophectoderm (TE, trophoblast) layer, an inner cell mass (ICM, embryo blast) and a blastocoel (fluid-filled cavity). The blastocyst inner cell mass is the source of true embryonic stem cells capable of forming all cell types within the embryo.

In humans, blastocyst stage of development occurs during the first and second week following fertilization (GA week 3 and 4) and is described initially as Carnegie stage 3. This stage is followed by blastocyst hatching and implantation.

One of the first key developmental patterning decisions in the morula to blastocyst development is TE or ICM cell fate. In the mouse model, Hippo[2](TEAD4) and Notch[3](Cdx2) together appear regulate this early fate decision.

Blastocyst Links: blastocyst | morula | fertilization | Week 1 | trophoblast | implantation | Human Day 3-6 Movie | Mouse Model Movie | Category:Blastocyst
  Molecular: Hippo | Notch
Mouse blastocyst development
Mouse blastocyst development[4]

Some Recent Findings

  • Four simple rules that are sufficient to generate the mammalian blastocyst[4] "We implemented experimentally reported mechanisms for polarity, cell-cell signaling, adhesion, and apoptosis as a set of developmental rules in an agent-based in silico model of physically interacting cells. We find that this model quantitatively reproduces specific mutant phenotypes and provides an explanation for the emergence of heterogeneity without requiring any initial transcriptional variation. It also suggests that a fixed time point for the cells' competence of fibroblast growth factor (FGF)/extracellular signal-regulated kinase (ERK) sets an embryonic clock that enables certain scaling phenomena, a concept that we evaluate quantitatively by manipulating embryos in vitro. Based on these observations, we conclude that the minimal set of rules enables the embryo to experiment with stochastic gene expression and could provide the robustness necessary for the evolutionary diversification of the preimplantation gene regulatory network."
  • Asymmetric division of contractile domains couples cell positioning and fate specification[5] "During pre-implantation development, the mammalian embryo self-organizes into the blastocyst, which consists of an epithelial layer encapsulating the inner-cell mass (ICM) giving rise to all embryonic tissues. In mice, oriented cell division, apicobasal polarity and actomyosin contractility are thought to contribute to the formation of the ICM. However, how these processes work together remains unclear. Here we show that asymmetric segregation of the apical domain generates blastomeres with different contractilities, which triggers their sorting into inner and outer positions."
  • Oct4 is required for lineage priming in the developing inner cell mass of the mouse blastocyst[6] "The transcription factor Oct4 is required in vitro for establishment and maintenance of embryonic stem cells and for reprogramming somatic cells to pluripotency. In vivo, it prevents the ectopic differentiation of early embryos into trophoblast. Here, we further explore the role of Oct4 in blastocyst formation and specification of epiblast versus primitive endoderm lineages using conditional genetic deletion. Experiments involving mouse embryos deficient for both maternal and zygotic Oct4 suggest that it is dispensable for zygote formation, early cleavage and activation of Nanog expression. Nanog protein is significantly elevated in the presumptive inner cell mass of Oct4 null embryos, suggesting an unexpected role for Oct4 in attenuating the level of Nanog, which might be significant for priming differentiation during epiblast maturation. Induced deletion of Oct4 during the morula to blastocyst transition disrupts the ability of inner cell mass cells to adopt lineage-specific identity and acquire the molecular profile characteristic of either epiblast or primitive endoderm. Sox17, a marker of primitive endoderm, is not detected following prolonged culture of such embryos, but can be rescued by provision of exogenous FGF4. Interestingly, functional primitive endoderm can be rescued in Oct4-deficient embryos in embryonic stem cell complementation assays, but only if the host embryos are at the pre-blastocyst stage. We conclude that cell fate decisions within the inner cell mass are dependent upon Oct4 and that Oct4 is not cell-autonomously required for the differentiation of primitive endoderm derivatives, as long as an appropriate developmental environment is established."
More recent papers  
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Older papers  
  • Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage[7] "We report studies of preimplantation human embryo development that correlate time-lapse image analysis and gene expression profiling. By examining a large set of zygotes from in vitro fertilization (IVF), we find that success in progression to the blastocyst stage can be predicted with >93% sensitivity and specificity by measuring three dynamic, noninvasive imaging parameters by day 2 after fertilization, before embryonic genome activation (EGA)."
  • Blastocyst gene expression correlates with implantation potential[8] "Compared with blastocysts that resulted in healthy fetal development, blastocysts that failed to implant (negative) showed decreased B3gnt5 and Eomes gene expression, while blastocysts that resulted in spontaneous pregnancy loss (absorption) displayed decreased Wnt3a and Eomes gene expression."
  • FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst[9] "Primitive endoderm (PE) and epiblast (EPI) are two lineages derived from the inner cell mass (ICM) of the E3.5 blastocyst. Recent studies showed that EPI and PE progenitors expressing the lineage-specific transcriptional factors Nanog and Gata6, respectively, arise progressively as the ICM develops. ... In conclusion, we propose a model in which stochastic and progressive specification of EPI and PE lineages occurs during maturation of the blastocyst in an FGF/MAP kinase signal-dependent manner."


Human Blastocyst

Human Blastocyst (day 3 to 6)
 ‎‎Day 3 to 6
Page | Play
Human blastocyst day 5-6.jpg
Page | Play
Human blastocyst hatching movie icon.jpg
Page | Play

Model Development

Model embryo to 32 cell stage icon.jpg
 ‎‎Morula Model
Page | Play
Model embryo to 128 cell stage icon.jpg
 ‎‎Blastocyst Model
Page | Play


Human Blastocyst Formation

The table below shows human blastocyst in vitro development changes during week 1.[10]

Human blastocyst formation-in vitro.jpg

Labeled Blastocyst

Human embryo day 5 label.jpg Human embryo day 5 label2.jpg

Blastocyst Hatching

Mouse Blastocyst hatching[11]
Mouse-hatching blastocyst.jpg Human carnegie stage 3 label.jpg
Blastocyst hatching from zona pellucida (mouse) Blastocyst hatching from zona pellucida (human)

Model Human Blastocyst Development

The following figure is from a recent study[7] using video and genetic analysis of in vitro human development during week 1 following fertilization.

Model human blastocyst development.jpg

  • EGA - embryonic genome activation
  • ESSP - embryonic stage–specific pattern, four unique embryonic stage–specific patterns (1-4)
Links: Figure with legend

Mouse Blastocyst Gene Expression

Mouse- preimplantation gene expression.jpg

General gene expression patterns are indicated from genomic profiling.[12]

  • red - loss of maternal mRNAs
  • green - activation of embryonic genome (EGA)
  • purple - maternal gene activation (MGA)
  • orange - continuous expression

Inner Cell Mass

Human Blastocyst (day 5)[1]

This outer layer of cells is also called the "embryoblast", a cluster of cells located and attached on one wall of the outer trophoblast layer.

Trophoblast Layer

This outer layer of cells is also called the "trophectoderm" (TE) epithelium. A key function is for the transport of sodium (Na+) and chloride (Cl-) ions through this layer into the blastocoel.

Differentiation of this layer has been shown to be regulated by the transcription factors Tead4[13] and then Caudal-related homeobox 2 (Cdx2).

Links: Trophoblast | OMIM -Tead4 | OMIM - Cdx2

Blastocoel Formation

Mouse - blastocoel formation[12]
  • trophectoderm transports of Na+ and Cl- ions through this layer into the blastocoel
  • generates an osmotic gradient driving fluid across this epithelium
  • distinct apical and basolateral membrane domains specific for transport
  • facilitates transepithelial Na+ and fluid transport for blastocoel formation
  • transport is driven by Na, K-adenosine triphosphatase (ATPase) in basolateral membranes of the trophectoderm [14]

Blastocyst Metabolism

Mouse blastocyst GLUT8 expression.[15]

At the blastocyst stage, mammalian development metabolism switches on anaerobic glycolysis metabolism to satisfy metabolic demands of growing blastocyst and formation of the blastocoel. This is thought to be driven by the integral membrane protein family of facilitative glucose transporters (GLUT or SLC2A).

  • aerobic - oxidation of lactate and pyruvate via the citric acid cycle (Krebs cycle) and oxidative phosphorylation
  • glycolysis- converts glucose into pyruvate
  • GLUT - GLUcose Transporter (divided into 3 classes I-III)
  • SLC2 - Solute Carrier Family 2

Glucose Transporter Expression

  • GLUT1 - from zygote to blastocyst. (all mammalian tissues, basal glucose uptake)
  • GLUT2 and GLUT3 - from late eight cell stage to blastocyst. (GLUT2, liver and pancreatic beta cells; GLUT3, all mammalian tissues, basal glucose uptake)
  • GLUT4 - not expressed. (muscle and adipose tissue)
  • GLUT8 - up-regulated at blastocyst stage. (central nervous system and heart)
(Data mainly from mouse development, adult tissue expression shown in brackets)

A mouse study,[15] has shown GLUT8 is up-regulated following insulin stimulation, though a more recent GLUT8 knockout mouse shows normal early embryonic development in the absence of this transporter.[16]

Links: Biochemistry - glucose transporters | GLUT1 | GLUT2 | GLUT8

Blastula Cell Communication

Two types of cell junctions have been identified located at different regions in the developing blastocyst.

Tight junctions

Located close to outer surface create a seal, isolates interior of embryo from external medium.

Gap junctions

Allow electrically coupling of the cells of epithelium surrounding the fluid-filled cavity.

Tight junction 01.jpg Gap junction 01.jpg
Adhesion EM Images: GIT epithelia EM1 | GIT epithelia EM2 | GIT epithelia EM3 | Desmosome EM
Adhesion Cartoons: Tight junction | Adherens Junction | Desmosome | Gap Junction

Blastocyst Hatching - zona pellucida lost, ZP has sperm entry site, and entire ZP broken down by uterine secretions and possibly blastula secretions.

Uterine Glands - secretions required for blastocyst motility and nutrition

Links: MBoC Figure 21-69. The blastula

Blastocyst Hatching

At about day 5 the human blastocyst "hatches" out of the protective zona pellucida. This hatching allows increased growth, access to uterine nutrient secretions and blastocyst adhesion to the uterine lining. Associated with this hatching process are a series of physical contractions.

In the blastocyst, repeated contractions occur after blastocoel formation and the frequency of contractions is greater during the hatching period than in the periods both before and after hatching.[17] Interestingly, the same researchers in this mouse study suggest that the weaker contractions (less than 20% volume reduction) seen have a role in hatching, in contrast to strong contractions (20% or more volume reduction) have the opposite effect of inhibiting hatching.

In the mouse model, the identified sites of zona pellucida shedding varied (24% mural site, 24% inner cell mass site, 17% equatorial site, and 35% other sites).[18]

Links: Blastocyst Day 5-6 Movie
<mediaplayer width='500' height='450' image="http://php.med.unsw.edu.au/embryology/images/a/af/Human_blastocyst_day_5-6.jpg">File:Human_blastocyst_day_5-6.mp4</mediaplayer>

Human blastocyst contractions (day 5-6)[7]

Molecular Factors

  • TEA DNA- binding domain, these factors bind to the consensus TEA/ATTS cognate binding site[19]
    • TEF-3 - renamed Tead1 and Tead4
    • Tead3 - is expressed in the placental syncytiotrophoblasts
  • E-cadherin - Calcium ion-dependent cell adhesion molecule, a cell membrane adhesive protein required for morula compaction
  • epithin - A type II transmembrane serine protease, identified in mouse for compaction of the morula during preimplantation embryonic development. Expressed from 8-cell stage at blastomere contacts and co-localises in the morula with E-cadherin.[20]
  • Na, K-adenosine triphosphatase - A sodium potassium pump that generates an osmotic gradient for fluid flow into the blastocoel
  • Zonula occludens-1 - (ZO-1) Tight junction protein involved in morula to blastocyst transformation in the mouse [21]

Blastocyst in Other Species

Mouse Blastocyst

Early mouse development cartoon.jpg

Early mouse development model[23]

Links: Mouse Development

Bovine Blastocyst

Links: Bovine Development


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  2. Sasaki H. (2015). Position- and polarity-dependent Hippo signaling regulates cell fates in preimplantation mouse embryos. Semin. Cell Dev. Biol. , 47-48, 80-7. PMID: 25986053 DOI.
  3. Rayon T, Menchero S, Nieto A, Xenopoulos P, Crespo M, Cockburn K, Cañon S, Sasaki H, Hadjantonakis AK, de la Pompa JL, Rossant J & Manzanares M. (2014). Notch and hippo converge on Cdx2 to specify the trophectoderm lineage in the mouse blastocyst. Dev. Cell , 30, 410-22. PMID: 25127056 DOI.
  4. 4.0 4.1 Nissen SB, Perera M, Gonzalez JM, Morgani SM, Jensen MH, Sneppen K, Brickman JM & Trusina A. (2017). Four simple rules that are sufficient to generate the mammalian blastocyst. PLoS Biol. , 15, e2000737. PMID: 28700688 DOI.
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Cite this page: Hill, M.A. (2021, March 5) Embryology Blastocyst Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Blastocyst_Development

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