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Fate and potency (1)
Concepts of developmental biology
DEVELOPMENT: A BLEND OF DIFFERENT PROCESSES
Cell division
Embryonic cleavage vs somatic divisions
1. Somatic cell cycle
└ G1 → Synthase → G2 → Mitosis
└ Around 16 hours
└ Because there is no pressure from outside
2. Embryonic cleavage cycle
└ S→M
└ Extremely short, around 30 minutes
└ The embryo has no time to grow during cleavage stages
→ No time to synthesize proteins
→ Need to develop fast because of dangerous environment (out of mother)
→ It invests in generating more cells
→ Exponential increase in cells in a short time frame
Patterns of embryonic cleavage
- What determines the pattern
└ Amount and distribution of yolk protein within cytoplasm
└ Factors in egg cytoplasm influence the angle of mitotic spindle & timing of its
formation
1. Mammals
└ Isolecithal rotational cleavage
2. Amphibians
└ Centrolecithal superficial cleavage
└ Cleavages are complete
└ Size of cells is not equal because there is a lot of yolk → upper part is less heavy,
faster cleavage
3. Fish
└ Telolecithal discoidal cleavage
└ Embryo develops a disc on top of the yolk
4. Insects
└ Centrolecithal superficial cleavage
└ Nuclei divide but membranes do not → lots of nuclei in 1 cell
└ Nuclei organize in the outer area of the cell
1
,Activation of zygotic genome
- Zygotic genome = genome that is a result of the homologous recombination between the
maternal and paternal chromosome
- Maternal mRNAs are laid down in the oocyte during oogenesis, after fertilization new
proteins are synthesized from the maternal mRNA
- Transcription from the embryo’s own genes (zygotic genome) starts
└ Mouse: activated at the 2 cells stage
└ Human: 8-16 cells stage
└ Frog: from 12 cleavages onwards
Difference between species: some embryo’s need to become fast independent
because there are predators, they aren’t safe in the womb of the mother
Differentiation = process by which an unspecialized cell becomes specialized into one of the many
cell types that make the body (specification & determination)
Historical perspective
- Scientists had 2 opposing theories on how cells became differentiated:
1. Restriction = cells lost all genes except those relevant to their task
2. Potency = cells keep all the genes and selectively turned genes on or off
- Experiment Hans Spemann and Hilde Mangold:
1) Make a knot of hair around salamander embryo
2) Isolation of 1 nucleus in 16 cell stage
3) Two independent embryo’s develop
→ 1 cell of 16 cell stage has a whole potency
to complete a whole embryo = totipotent
Waddington’s epigenetic landscape
- At the top of the hill: pluripotent undifferentiated stem cell
- At the bottom of the valley: terminally differentiated cell
- Fate choses occur at bifurcation points
- The furrows: cells follow paths that may be predetermined
2
,Germ layers
- Increase in organizational complexity of the embryo happens gradually
- First the embryo generates a couple of distinct regions & within these germ layers the fate of
the cells then becomes progressively laid down
1. Ectoderm
└ Epidermis
└ Central nervous system
2. Mesoderm
└ Cardiovascular system
└ Urogenital system
└ Muscles
└ Bone and cartilage
3. Endoderm
└ Gastrointestinal system and associated organs
└ Lungs
Potency = what a cell still can become
1. Totipotent = describes the capacity of a cell to form all cell types of an
organism, including extraembryonic tissues
2. Pluripotent = cells of the developing embryo that will give rise to
ectoderm, mesoderm or endoderm
3. Multipotent = cells that can give rise to different cell types belonging to
the same germ layer
Specification = the first stage of commitment of a cell or tissue fate during
which the cell or tissue is capable of differentiating by itself
- Cell fate can be altered by another environment or by other neighbours
- They are not yet differentiated
- Can be tested when isolated and cultured in a neutral milieu:
1) Take square of the tissue of a frog embryo
2) Take animal cap
3) Culture animal cap without additional factors and with additional factors
3
,Determination = irreversible stage of commitment following specification
- The determined stage is when a cell or tissue is capable of differentiating autonomously even
when placed into a non-neutral environment
- When a cell type or tissue is determined, it will not change fate anymore
- Testing determination by transplantation to another location and follow up what it becomes:
1) Take the presumptive eye region of a gastrula
& label it with green dye
2) Transplantation into the trunk of a neurula
3) Cells become structures typical for the trunk
→ Cells had not been determined
1) Take the presumptive eye region of a neurula
& label it with green dye
2) Transplantation into the trunk of a neurula
3) Cells become an eye
→ Cells had already be determined
In summary
- Extracellular signals and cues trigger changes in gene expression
- A small number of genes (often TFs) that are expressed in different combinations can specify
many different cell types
- A single TF can regulate expression of different genes in a positive or negative fashion
- Differential gene expression
└ Every somatic cell nucleus contains complete genome
└ Unused genes are not destroyed or mutated
└ A small portion of the genome is expressed in each cell
└ A small portion of this portion is specific for that cell type
- The characteristic proteome of a cell is the result of
└ Differential gene expression
└ Selective pre-mRNA processing
└ Selective mRNA translation
└ Differential posttranslational protein modification
Growth
- How do cells know when to stop dividing?
- Growth is disproportional
- Different cell types have different size
4
,Migration
Five types of cell migration
1. Invagination
└ Infolding of a sheet of cells
└ Much like the indention of a soft rubber ball when its poked
└ Ex. Sea urchin endoderm
2. Involution
└ Inward movement of an expanding outer layer
└ It spreads over the inner surface of the remaining external cells
└ Ex. Amphibian mesoderm
3. Ingression
└ Migration of individual cells from the surface into the embryo’s interior
└ Individual cells become mesenchymal and migrate independently
└ Ex. Fruitfly neuroblast cells
4. Delamination
└ Splitting of one cellular sheet into two more or less parallel sheets
└ Ex. Hypoblast formation in birds
5. Epiboly
└ Movement and spreading of an epithelial sheet
└ Usually ectodermal cells
└ To cover the whole embryo
└ Ex. Ectoderm formation in amphibians
Patterning = set of processes by which embryonic cells form ordered spatial arrangements of
differentiated tissues
- The process that establishes a well-ordered spatial pattern of cells and tissues
- Examples of patterning
1. Establishment of a body plan
└ Head anterior
└ Tail posterior
└ An axial nervous system
└ Limbs lateral
2. Asymmetric positioning of the hearts
3. Stereotypical pattern of different neurons in neural tube
4. Stripes of zebra
5
,Morphogenesis = process of making changes in form of the embryo
- Usually occurs with patterning
- Involves
└ Cell growth
└ Cell migration
└ Cell death
Morphogenic processes regulated by mesenchymal cells
PROCESS ACTION MORPHOLOGY EXAMPLE
Cell division Mitosis produces more cells Limb mesenchyme
(hyperplasia)
Cell death Cells die Interdigital
mesenchyme
Migration Cells move at particular times and Heart mesenchyme
places
Matrix Synthesis or removal of extracellular Cartilage mesenchyme
secretion and layer
degradation
Growth Cells get larger (hypertrophy) Fat cells
Morphogenic processes regulated by epithelial cells
PROCESS ACTION MORPHOLOGY EXAMPLE
Dispersal Epithelium → mesenchyme Müllerian duct
(entire structure) degeneration
Delamination Epithelium → mesenchyme Chick hypoblast
(part of structure)
Shape change Cells remain attached as morphology Neurulation
or growth is altered
Intercalation Rows of epithelia merge to form Vertebrate gastrulation
fewer rows
Division Mitosis within row or column Vertebrate gastrulation
Matrix Synthesis or removal of extracellular Vertebrate organ
secretion and matrix formation
degradation
Migration Formation of free edges Chick ectoderm
Apoptosis = programmed cell death is a critical and physiological part of normal embryonic
development
6
,CLEAVAGE STAGES
Early development in mammals
- Oocytes of mammals are amongst the smallest oocytes in animal kingdom
- Development inside another organism
- Need for supportive extraembryonic tissues
└ Placenta, umbilical cord, yolk sac and amnion
Cleavage divisions
Two rounds of differentiation
1. Compaction = a unique feature of mammalian cleavage embryos
└ Difference between inner and outer cells
└ Blastomeres around the 8-cell stage flatten and microvilli become confined to the
outer surface of the ball of cells
└ Green cells become trophectoderm = feeding cells (placenta, chorion)
└ Purple cells are ICM cells = pluripotent
2. Cavitation = cavity filled with fluid pushes cells to 1 side
└ Trophectoderm forms blastocoel cavity
└ Initiated by diffusion of water across osmotic gradients and transport of water
through aquaporins
└ Location of blastocoel cavity determines embryonic-abembryonic axis
└ Red cells = epiblast cells that stay pluripotent, derive the whole embryo
└ Blue cells = primitive endoderm, support tissue
7
,Specification of embryonic and extraembryonic lineages
- Embryo can start growing after implantation
- In order to implant, the embryo must come out of its zona pellucida
- Blue cells = embryo epiblast
- Other cells = extraembryonic tissues
- Fate decisions are influenced by heterogeneity at 4-cell stage (but not determined)
Wave 1: cell divisions result into inside and outside cells
- Outside cells = extraembryonic trophectoderm (TE)
└ Tightly adhered via tight junctions
└ Polarized along apical-basal axis
└ Asymmetric cell-cell contacts
- Inside cells = pluripotent inner cell mass (ICM)
└ Symmetric cell-cell contact prevents establishment of an apical domain
Wave 2: cells of ICM segregate into
- Extraembryonic primitive endoderm (PE)
- Pluripotent epiblast (EPI)
8
,Two cell fate decisions by activation of different TFs
1. First cell fate decision
└ Outer cells become trophectoderm cells
→ Cdx2 activation: inhibition of Oct4
└ Inner cells become inner cell mass cells
→ Start to produce Fgf4
→ Cells that end up in ICM in wave 2 express receptors for Fgf4 (fgfr2)
→ Oct 4 activation
2. Second cell fate decision
└ Primitive endoderm cells
→ Receptor activates MAPK: inhibition of NANOG so activation of GATA6
└ Epiblast cells
→ NANOG is expressed and keeps GATA6 under control
Principle of gatekeeper TFs
- Whenever cells become specified/determined in another cell lineage/cell type, they will
express TFs that
└ Induce and enforce expression of lineage-own genes
└ Repress TF genes of the other/former lineage
- For a factor to be a true gatekeeper TF, its loss-of-function should be capable of reversing
lineage preservation, commitment and specification and restoring multipotent and/or
pluripotent differentiation capability
9
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