Branching morphogenesis in organs Flashcards
What organs is branching morphogenesis required in?
Examples?
Organs where a high surface area:volume ratio is needed
Lung Uteretic bud (gives rise to the kidney) Prostate Mammary gland Pancreas
What structure is formed in through branching morphogenesis?
Tree-like structure with a large surface area
What is the structure of the kidneys?
1000s of repeating units made of:
- Nephron
- Collecting duct
What is the collecting duct attached to in the kidneys?
At one end:
- Feeds into the nephron
At the other end:
- Connected to blood supply
In the kidney, what is the equivalent of the ‘twigs’ of the tree?
‘trunk’ of the tree?
Twigs - Collecting ducts
Trunk - Ureter
What is the DEFINATIVE kidney called?
The METANEPHROS
Where is the metanephros developed from?
The INTERMEDIATE mesoderm
What forms at the very posterior of each of the lines of intermediate mesoderm?
2 bud structures (one each side)
Called the URETERIC BUDS
Where are the ureteric buds formed from?
What type of cells are they made up from?
Formed from the intermediate mesoderm
Made up up epithelial-like cells
Where does the ureteric bud poke out into?
Into adjacent mesenchymal cells called the metanephric mesenchyme
What does the definitive kidney (metanephros) arise from?
From a result of RECIPROCAL INDUCTIVE interactions between the:
- Ureteric bud
- Metanephric mesenchyme
What is the metanephric mesenchyme sometimes known as?
The metanephric blastema
What are reciprocal inductive interactions?
1) One tissue signals to the 2nd tissue - causing the 2nd tissue to change
2) This newly changes tissue can now signal back to the 1st tissue and cause it to change
3) Happens repeatedly to build the kidney
Which structure of the developing kidney undergoes branching morphogenesis?
How?
The ureteric bud
Receives signals from the metanephric mesenchyme
What are the steps of branching morphogenesis of the ureteric bud?
1) GDNF signals from the MM cause PROLIFERATION and OUTGROWTH of the ‘tip cells’
2) Ureteric bud ‘bulges’
3) Cells in the middle to the tip of the ureteric bud see MORE of the signal
HOWEVER, this causes these leading-edge tip cells to ARREST proliferation - causing the tip of the bud to flatten
4) Lateral tip cells continue to proliferate - resulting in the formation of a cleft, with 2 tips (a branch)
5) Lateral tips are still surrounded by the mesenchyme - process repeats
What receptors do the cells of the ureteric bud have?
What is it called?
What type of receptor is it?
GDNF receptors
Called Ret
A receptor tyrosine kinase
What happens when GDNF binds to Ret in one the bud cells?
- Signalling transduction pathway
- Up regulation of core TRANSCRIPTION FACTORS
- Up regulation of more signalling pathways
Why does the ureteric bud begin to bulge?
Ureteric bud cells in the tip proliferate in response to GDNF but cannot move as they are EPITHELIAL
What do the new signals in the epithelial cells of the ureteric bud act on?
Some signals act back onto the mesenchyme
BUT some signals act back onto the epithelial cells:
- To help regulate gene expression profiles and govern the response of the cell
- To help lead to bifurication
What responses of the epithelial cells help lead to bifurication?
- Local proliferation
- Orientated cell division
- Cell migration
- Cell adhesion
- Cell shape
- ECM remodelling
What happens are the same time as the metanephric duct signalling to the ureteric bud, causing it to branch?
What does this cause?
The ureteric bud signals to LOCAL parts of the metanephric mesenchyme
Causing the cells to CONDENSE and undergo a MTE transition, to form RENAL EPITHELIUM and then RENAL VESICLES
What do renal vesicles form?
How?
Form nephrons
How:
- Grows into a comma-shaped body
- Becomes S shapes body
- Gets longer and longer
- At one end - fuses with the collecting duct
- At the other end - attracts endothelial capillaries (to form the Bowmann’s capsule)
- Ultimately, will get the complete nephron (at the S-shaped structure grows - it bends to form the loop of henle
Where is the collecting duct that the S shaped renal vesicle fuses with?
The tip of the ureteric bud
How does the distal end of the renal vesicle fuse with the ureteric bud?
By selective apoptosis
How is the proximal end of the renal vesicle polarised?
Provides local signals for angiogenesis - so that capillaries form
How many renal vesicles fuse in each kidney?
10^6
How can we study the process of branching morphogensis in the kidney in ‘real time’
Using transgenic animals:
- Clone promoter (that normally drives a gene expressed in the ureteric bud) UPSTREAM of GFP
- Ureteric bud that forms then glows green
Where did the understanding of branching morphogenesis in the lungs come from?
Through analysis of drosophila tracheal development
If branching of the trachea a conserved process?
Yes
What 2 tissues do the lungs develop from?
The mesoderm and endoderm
What parts of the lungs do the endoderm give rise to?
How?
Epithelial lining of the trachea, larynx, bronchi, alveoli
Through branching morphogenesis
Where is the mesoderm of the lungs present?
What does it give rise to?
Present around the tips of the developing buds
Give rise to:
- Cartilage
- Muscle
- Connective tissue
What structure do the trachea, bronchi, bronchioles etc. develop from?
What is this?
From the RESPIRATORY DIVERTICULUM
An ENDODERM bud that grows out from the ESOPHAGUS
What happens to the tip of the respiratory diverticulum?
What does this form?
Undergoes branching morphogenesis - first branches go left and right
Forms the lung buds
When do the lung buds form in humans?
About the 4th week
What cells is the respiratory diverticulum made from?
Endothelial epithelial cells
What is outgrowth of the respiratory diverticulum dependant on?
What do these signals do?
- Signals from the adjacent mesoderm/mesenchyme
- Which act on the receptors in the respiratory diverticulum and tell the cells to proliferate
- Causing the tube to get longer
What always surrounds the lungs/respiratory diverticulum?
Sac of mesoderm
In the lungs, what do the mesenchymal cells express?
FGF10
In the lungs, what does the respiratory diverticulum express?
FGF receptor
What is the process of branching morphogenesis in the lungs?
1) Endothelial epithelial cells (express FGFR) respond to the secretion of FGF from the nearby mesenchyme by PROLIFERATING
- Causes bud formation and extension towards the FGF source
2) Cells are the leading tip see the highest concentration of FGF
- Causing the expression of secondary genes in the tip
- Turning the leading tip into a signalling centre
3) BMP4 expressed at the highest levels in the ‘leading edge’ tip cells
- Autonomously inhibits epithelial cell proliferation
- Causing flattening of the of the bud
4) At the same time, shh expressed by the leading tip cells diffuses into the mesenchyme and INHIBITS FGF10 expression in the mesenchyme closest to the tip
- This SPLITS FGF10 expression - so that is surrounds the tips and promotes the next round of branching
What are the secondary genes that are expressed in the leading tip as a result of seeing the highest concentration of FGFs?
BMP4
Shh
What does ‘Sprouty’ do?
Why?
Limits the action of Fgf10
So the branching is RESTRICTED to the TIP of the branch
What is the expression of Sprouty induced by?
FGF10 over a long time period (after it has induced shh and BMP4 signalling)
What type of feedback loop is between Fgf10 and sprouty?
Negative feedback
Fgf10 induces its own inhibitor - to limit its time of action
What else occurs during branching in the lung?
Why?
Recruitment of blood capillaries
For gas exchange
What fraction of the adult alveoli are present at birth?
What does this show?
1/6
Shows that respiratory bronchioles and alveoli continue to increase in number after birth
Where are the ureteric bud and the metenephric mesenchyme derived from?
The intermediate mesoderm
What does shh released from the leading tip cells do?
- Inhibits FGF10 expression at in the mesoderm/mesenchyme closest to the tip
- Splitting Fgf10 expression - promoting next round of branching
