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D&D > Cell fate and Hippo pathway > Flashcards

Cell fate and Hippo pathway Flashcards

1
Q

What happens before the development of the embryo proper?

A

The conceptus must first implant, then generate the “germ” disc- takes ~10 days.

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2
Q

What is gastrulation?

A

From 2 layers to 3; the hypoblast (primitive endoderm) is displaced by involuting cells that become definitive endoderm and mesoderm.

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3
Q

Between the morula stage to the blastocyst, what occurs between cells?

A

Compaction

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4
Q

What are the first steps in neurulation?

A

Notochord signalling to overlying ectoderm to form the neural plate, anterior to the primitive streak.

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5
Q

What is the “silk purse” model?

A

Neurulation is concomitant with other form-shaping processes, particularly gut formation and body folding in the silk purse model.
Involves folding; open with cord round margins, then folding to for, pirse ‘neck’.
Septum and heart move from margin to centre.
Yolk sac, allantois and stalk make umbilical cord. Prochordal and cloacal plates delimit gut tube.

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6
Q

Describe the second cell fate

A

ICM–> Epiblast or Hypoblast (primitive endoderm)

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7
Q

What does the epiblast differentiate into?

A

Epiblast–> embryonic epiblast or amnionic ectoderm

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8
Q

What does the embryonic epiblast differentiate into?

A

Embryonic epiblast:

  • -> embryonic ectoberm
  • ->primitive streak–> embryonic endoderm
    - -> embryonic mesoderm
    - -> extraembryonic mesoderm
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9
Q

What are the theories of how cell fate is determined?

A
  1. mosaic development- information inherited from parental cell e.g. Roux’s hot needle experiment
  2. Regulative development- cell influenced by surroundings/position within embryo e.g. Driesch’s separation of sea urchin blastomeres
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10
Q

What are the points on mosaic vs regulative development?

A
  • Developmental decisions are not simply based on these binary options
  • More complex interactions exist and provide a combination of these two mechanism
  • These can provide robustness in embyronic development
  • e.g. Roux’s experiment, when repeated with a a
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11
Q

What is cell fate?

A

What will normally happen to a cell during development

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12
Q

What does commitment comprise of?

A
  • Specification- what tissues will develop in an autonomous (“neutral”) environment
  • Determination- an irreversible change in potential
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13
Q

What is differentiation?

A

A restriction of potential with molecular/biochemical changes- term often used for mature cell types

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14
Q

What is potential or potency?

A

The range of tissues which a cell can give reise to:

  • Totipotent- can give rise to all tissues
  • Pluripotent- can give rise to many tissues
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15
Q

How can you establish fate and commitment?

A
  • label a region in a donor (early)–> either perform (a) an orthotopic graft- observe normal fate (b) isolation of cells to see specification (c) heterotopic graft to see determination
  • label a donor late–> do a alate heterotopic graft–> see its determination
  • mark or label cells so they can be distinguished later
  • direct observation (limited application)
  • chemical markers - vital dyes (nile blue sulphates- surface, Dil/Dio, fluorescent dextrans/enzymes e.g. horseradish peroxidase),
  • gentic markers e.g. GFP/beta-galactosidase (retroviruses, chimeras, ttransgenics)
  • clonal analysis- labelling individual cells to test potential - DiL/DiO/LacZ (beta-galactosidase)
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16
Q

What is induction?

Give an example

A

Restriction in potential often depends on inductive interactions from neighbouring cells.

e. g. neural tube patterning by notochord
e. g. xenopus mesoderm induction

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17
Q

What is competence?

A

Ability to respond to an inductive signal

18
Q

Name the types of inductive interactions

A
  1. Permissive- so add a fator, induce a new cell fate
  2. instructive- appositional - so something is applied to the cell to signal it (e.g. notochord and floor plate) or morphogen gradient
19
Q

Describe morphogens

A

Morphogens ae diffusable molecules that trigger different cell fates at different concentration/

Gradients need to be formed within the embryo and cell fate which is changed accordingly.

Can provide positional information within the embryo.

20
Q

What are homeotic genes?

A

They regulate the development of anatomical structures (identified in insects to control segment identity).

E.g. theoretical animal with 4 segments, specified by morphogen gradient that sequentially activates genes 1-3
Homeotic effects of altering morphoen gradient or blocking morphogen.

21
Q

How are changes in cell fate reflected by changes in gene expression?

A

Secreted factors and other signals allow cells to communicate.
Often results in regulation of gene expression.
Individual transcription factors don’t act alone, so effects can vary in different cell types.
Additional control at elvel of translation, post-translation, epigenetic changes.

22
Q

What 2 factros are key for successive waves of tissue specification in the sea urchin embryo?

A

Wnt 8 and Blimp1

23
Q

What genes are expressed in the ICM?

A

Oct3/4, Sox2, Sall4, Nanog

24
Q

What genes are expressed in the trophectoderm?

A

Cdx2, Gata4, Tead4

25
Q

How are the intial differences established between cells of the embryo?

A

Asymmetry, polarisation and inside/outside.

26
Q

Explain the asymmetric Cdx2 mRNA localisation in polarised blastomeres

A

Cell polarisation causes symmetry-breaking.
mRNA for Cdx2 TF is assymmetrically localised at the cortex of polarised blastomeres–> cells divide symmetrically, mRNA= equally partitioned between daughter cells.
If asymmetrical, outer daughter cells inherit more Cdx2 mRNA than inner cells.

27
Q

What does Hippo signalling mediate?

A

Cell position-dependent differentiation by Tead4 expression

28
Q

Explain what happens in the Hippo pathway in the ICM

A

Hippo signalling activated: Yap1 is phoshporylated by Lats so Yap1-P cannot translocate to the nucleus and cannot activate Tead4.

29
Q

Explain how Hippo signalling works in the trophectoderm

A

Polarity/apical signals suppresses Hippo Signalling so Lats doesn’t phosphorylate Yap1 so it can translocate to the nucleus and interact with Tead 4 and TE specific target genes e.g. Cdx2

30
Q

Explain how ICM and TE transcription factors interact with eachother?

A

TE expresses Tead4 –> increases expression of Cdx2 and Gata 3 –> all these specificy the TE

Double negative feedback loop:
ICM- expresses Oct3/4 and Nanog which increases more Oct3/4 and Nanog expression and INHIBITS Cdx2- makes Cdx2 expression restricted to TE. Cdx2 inhibits Oct3/4 and Nanog (hence double -ve feedback).

Oct3/4 and Nanog= ICM only

31
Q

What controls cell polarity, Hippo signalling and cell positioning in 16-cell stage mouse embryos?

A

Par-aPKC dependent and independent mechanisms

32
Q

Desribe Oct4 kinetics in the ICM vs TE

A

Oct4 DNA binding sites differ amongst cells (because of chromatin structure).

Excess of factor = segregation of Oct-paGFP kinetic properties before lineage allocation.

Cells with slower kinetics and large immobile fraction divide more frequently (assymetrically) during 8–>16 cells stage which increases cells to pluripotent lineage.

Faster cell kinetics and small immobile fraction= extra-embryonic lineage though symmetrical division.

E.g. Cell 1 of 4 cell embryo- has Oct4 protein, DNA and accessible Oct4 sites- results in slow Oct4 kinetics and asymmetric cell division so produce one inside and one outside daughter cell. Cells with low Oct4 kinetics will preferentially divide asymmetrically to generate ICM and TE progenitors.

Cell 2 of 4 cell embryo- has Oct4 protein, DNA, accessible Oct4 sites and inaccessible Oct4 sites–> causes fast Oct4 kinetics and symmetric cell division of TE only. Cells with high Oct4 kinetics will preferentially divide symmetrically will generate TE progenitors.

33
Q

How early may differences in cell fate begin and what is observed?

A
  • As early as 4-cell stage
  • Some cells have histone methylation which allows binding of TFs e.g. Oct4 and Sox2–> allows pluripotency of genes e.g. Sox2, Nanog= ICM
  • Some cells have histones that aren’t methylated and don’t bind TFs and differentiate with genes e.g. Cdx2= TE
34
Q

What reinforces early differences in gene expression?

A

DNA and histone methylation

35
Q

Summarise facts on ICM vs TE

A
  • Early differences in gene expression exist between blastomeres, probably from the 4-cell stage
  • early blastomeres express genes for both ICM and TE cell fates that become refined as development proceeds
  • gene expression levels arent constant
  • polarity, methylation, feedback loops, mutual inhibiton all serve to reinforce differences, permit regulative development and establish commintted cell fates.
36
Q

Describe segregation of the ICM

A

Formation of the epiblast and primitive endoderm (hypoblast)

Epiblast and PE progenitors are initially distributed throughout the ICM

Segregation of cell populations so that PE cells are adjacent to blastocoele.

37
Q

What factors are central in control of the second fate decision?

A

Gata6 and FGF4

  • Sox17 is a marker of PE/hypoblast
  • Nanog is a marker of epiblast
  • Sox17 not present in absence of Gata6
  • Nanog not present when excess FGF4 is added
38
Q

Describe chimera technique for fate mapping:

A
  • Quail chick chimeras- combined tissue from different embryos
  • quail tissue- label DNA to distinguisg from chicken
  • Dye labelling and grafting
39
Q

How was Hippo first identified?

A

as a tumour supressor in Drosophila

Mutation causes overgrowth

Mouse homologues known as Mst1 and 2

40
Q

What causes Hippo signalling during preimplantation during mouse development?

A

-Compaction of cells–> polarity at apical surface–> polarity= outer cell differentiation–> Cdx2 and Gata3- TE

Basal part of cell is not polar–> Cdx2/Gata3/Oct3/4/Nanog–> inner cell (apolar)–> Sox2/Oct3/4/Nanog = ICM

Cell-cell adhesion= Hippo active–>Yap1-p–>cannot translocate to nucleus–> Tead= off

No cell-cell adhesion–> hippo inactive–> Yap unphosporylated–> translocates to nucleus–> activates Tead so TE gene expression turns on

Mst1 is activated only in cells in the centre of the embryo (probably by differences in cell-cell contact). Mst1 activation inhibits Yap and therefore prevents Tead4 activity

D&D (7 decks)

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