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Embryology > Cell fate > Flashcards

Cell fate Flashcards

1
Q

What is a morula?

A
  • Zygote undergoes mitosis to produce more cells
  • Forming a morula which is of 16 totipotent cells
  • Occurs in the first few days within 1 week of fertilisation
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2
Q

What is blastocyst?

A
  • 200 to 300 cells (pluripotent/totipotent)
  • Trophoblasts/trophoectoderm and embryoblasts form
  • Trophoectoderm on the outside surrounding the inner mass of cells of embryoblasts
  • Blastocoel is present (fluid filled space)
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4
Q

When do inner cell mass and trophoectoderm become apparent?

A

It becomes apparent in blastocyst stage but molecular changes occur before this

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5
Q

What do embryoblasts give rise to/differentiate into?

A

Bilaminar germ disc formation- occurs at week 2 after fertilisation
Epiblast - gives rise to proper embryo
Hypoblast - gives rise to extraembryonic tissue and yolk sac

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6
Q

When do the 2 cell fate decisions take place?

A
  • Before implantation
  • It allows setting apart of the extraembryonic lineages like trophoectoderm and primitive endoderm (hypoblast) from pluripotent progenitors of the future body (embryoblasts and epiblast)
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7
Q

What type of cell are epiblast?

A

Columnar cells

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8
Q

What kind of cell division causes the formation of inner cell mass progenitor cells (embryoblasts) and trophoectoderm to form?

A

Causes by 2 successive waves of asymmetrical cell division

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9
Q

Is the hypoblast (primitive endoderm) or epiblast closer to blastocoel?

A
  • Hypoblast is closer to the blastocoel

- Epiblast is on the other side

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10
Q

What 5 things are associated with the 1st and 2nd cell fate decisions?

A
  1. Mrna degradation
  2. Minor and major phases of zygomatic genome inactivation (ZGA)
  3. Cell polarisation
  4. Waves of asymmetrical divisions
  5. Onset of gene expression patterns
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11
Q

How are initial differences established?

A
  1. Presence of zona pellucida are means some cells are pushed in the centre whilst some are forced to the outside
  2. Cells can divide symmetrically or asymmetrically
  3. By cell 16, we already have an inner and outer layer
  4. Outer cells develop polarity and express epithelial phenotype during compaction
  5. As embryo becomes blastocyst, there’s potential for differences between those in inner cell mass. Some cells will lie closer to blastocoel so it may receive signals from it. Some cells will be closer to trophoectoderm and may receive signals from there
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12
Q

What are the 2 cell fate decisions?

A
  1. Formation of inner cell mass and trophoectoderm

2. Formation of epiblast and hypoblast from inner cell mass/embryoblasts

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13
Q

What is the differentiation of trophoectoderm associated with (transcription factors)?

A
  • GATA4
  • TEAD4
  • Cdx2
  • These stimulate Elf5 expression which positively feeds back to increase TEAD4 and Cdx2
  • Cdx2 inhibits Oct4 and Nanog
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14
Q

What is the differentiation of ICM associated with (transcription factors)?

A
  • Nanog = drives differentiation of embryoblasts to Epiblast
  • Oct4
  • Oct3
  • Sox2
  • Sall4
  • GATA6 = drives differentiation to hypoblast
  • There is also positive feedback method
  • They inhibit Cdx4 production
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15
Q

What is the role of Cdx2?

A
  • Cdx2 is needed for trophoectoderm formation
  • Cdx2 mRNA is unevenly distributed within cells of early embryo, hence if cell undergoes symmetrical division, each daughter will inherit equal amounts of Cdx2 so retain their trophoectoderm characteristic
  • However, if they divide asymmetrically, one cell will receive all of the Cdx2 mRNA and the other would receive none
  • Cells in the inner part of embryo (inner cell mass) inherit less Cdx2 mRNA hence begin to lose their trophoectoderm characteristics
  • Cdx2 inhibits Oct4 and Nanog which are associated with inner cell mass differentiation. So cells that inherit less Cdx2 increases the expression of Oct4 and Nanog, leading to inner cell mass formation.
  • Cdx2 is regulated by TEAD4
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16
Q

What is the role of TEAD4?

A
  • Key regulator of trophoectoderm formation
  • It is needed for Cdx2 expression
  • it is expressed in both inner cell mass and trophoectoderm cells
  • It is only activated in trophoectoderm cells
  • Activation is controlled by polarity of cells via Hippo signalling pathway
  • In the inner cell mass, hippo signalling leads to phosphorylation of Yap1 by Lats Kinase which prevents TEAD4 from functioning in nucleus hence preventing Cdx2 from working, and prevents trophoectoderm formation
  • In the outside cells (trophoectoderm) hippo signalling is suppressed so Lats Kinase doesn’t phosphorylate Yap1, so unphosphorylated Yap1 can interact with TEAD4 to allow Cdx2 and GATA3 expression.
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17
Q

Why does signalling happen in inner cells and not outer cell (hippo pathway)?

A
  • Inner cells have lack of polarity so signalling occurs

- Outercells have polarity which alters the actin cytoskeleton and signalling is suppressed

18
Q

What is the role of Oct4?

A
  • This is involved in inner cell mass differentiation
  • Evidence from looking at Oct4 suggests polarity is present in embryo as early as cell 4 stage
  • Oct4 has different accessibility to binding to DNA due to differential chromatin structure
  • Experiments showed that some cells had fast decay of Oct4 within cells whilst others had slow decay
  • Fast decay indicated fewer accessible sites for Oct4 to bind so more Oct4 diffuses out
  • Slower decay indicates more accessible sites for Oct4 to bind so less Oct4 diffuses out
  • Faster decaying = divided symmetrically forming trophoectoderm cells (as more Oct4 diffuses out)
  • Slower decaying = dividing asymmetrically giving rise to trophoectoderm cells and inner cell mass
19
Q

What are the epigenetic modifications at the 4-cell stage?

A
  • Methylation of histone H3R26 helps binding of Oct4 and Sox2 to DNA by opening the binding sites, hence allowing ICM differentiation.
  • CARM1 is responsible for the methylation
  • Increased Oct4 and Sox2 binding promote increased transcription of pluripotency-related target genes e.g Sox21, Oct4 and Nanog -> this drives ICM lineage
20
Q

When do early expression in gene expression exist?

A
  • 4 cell stage

- Early blastomeres express genes for both inner cell mass and trophoectoderm cell fates that then become refined

21
Q

What are the other epigenetic changes?

A
  • DNA methylation of ICM at promoter region of Elf5, hence inhibiting trophoectoderm differentiation
  • There is no DNA methylation for Elf5 in trophoectoderm, there is only histone methylation and acetylation so increased Elf5 binding and increased Cdx2 expression, increasing trophoectoderm formation. There is a positive feedback loop.
  • In ICM, there is histone acetylation and methylation to promote the expression of Nanog, Sox2 and Oct4. There is a positive feedback loop.
22
Q

What is the evidence for polarity?

A
  • As the embryo divides, polarity of cells become more obvious
  • Initially, polarity is found through most of embryo but with increased divisions, polarity is only found in the outside of the embryo
  • By the time it’s a blastocyst, it has completely localised to where the trophoectoderm would be found
  • At the same time, changes in localisation of Yap can be seen
  • Initially, Yap is present within cytosol but as embryo becomes more polarised, Yap migrates to nuclei and is almost exclusively localised in the nuclei of trophoectoderm
23
Q

What is the cell fate decision 2?

A
  • Whether an ICM becomes epiblast or hypoblast (primitive endoderm).
  • GATA6 and FGF4 are central in control
24
Q

What is the segregation of the inner cell mass (ICM)?

A
  • Epiblast and primitive endoderm (hypoblast) are initially distributed through ICM
  • They become segregated so that the primitive endoderm cells are initially adjacent to blastocoel
25
Q

What are the 3 models for primitive endoderm formation?

A
  1. Induction Model = blastocoel sends out signals to cells close to it, causing them to differentiate and become primitive endoderm cells
  2. Sorting model = mitogens/gene expression patterns cause the primitive endoderm cells to relocate into random positions. They are sorted by gene expression patterns
  3. Combination model = mixture of induction and sorting
26
Q

What is the social mobility model?

A
  • Waves of assymetric divisions have a large effect on whether a cell will develop as an epiblast or primitive endoderm
  • Early wave of assymetric division gives rise to epiblast progenitors
  • Second wave gives rise to hypoblast progenitors
  • You get mosaic pattern, apoptosis occurs, to allow 2 distinct layers of form.
27
Q

Which transcription factors are involved in determining epiblast and hypoblast cell formation?

A
  • Ratio of GATA6 and Nanog
  • Nanog promotes epiblast differentiation. Nanog causes FGF4 production in epiblast.
  • GATA 6 promotes hypoblast differentiation
  • Epiblast and hypoblast communicate by FGF4 (secreted by Epiblast) which interacts with the FGFR2 of hypoblast. This activates Grb2 and Mack, increasing GATA6 expression in hypoblast. GATA 6 promotes hypoblast differentiation
  • In the early embryo, there are cells that express more Nanog and cells that express more GATA6
  • The cells that express more GATA6 express more FGFR. GATA6 inhibits Nanog
  • The cells that express more Nanog produce FGF-4
  • When FGF4 binds to FGFR, it causes a reduction in Nanog levels within cell which reinforces the changes
  • In the absence of FGF-4, we see that it cannot interact with the FGFR so there’s no FGF signalling to reinforce the production of GATA6 in hypoblast precursor cells.
28
Q

What are the 2 possible mechanisms for formation of multiple cell types and polarity (cell fate decision 1)?

A

Model 1: localised maternal determinant.
The maternal determinant is unevenly distributed in the oocyte (hence fertilised egg) and becomes inherited asymmetrically by daughter cells following cell division. It gives rise to 2 distinct cell populations and polarity within developing embryo (they’ll adopt different cell fates as one population will have the determinant and the other population will not)

Model 2: No localised maternal determinant
The difference within embryo has to arise by other means such as external factors may be responsible for kickstarting differentiation e.g. sperm entry point may affect polarity of zygote

Embryology (10 decks)

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