L16 - Branching Morphogenesis in Organs Flashcards
What organs is branching morphogenesis fundamental in?
Fundamental to function in many tissues where high surface area for exchange is required
- Lung – gas exchange
- Ureteric bud – gives rise to kidneys
- Salivary gland
- Prostate
- Mammary gland
- Pancreas
What is the overall kidney structure?
Composed of 1000s of repeating units made up of a nephron and collecting duct
- Collecting duct – feeds into the nephron
- Nephron – proximal and distal loops
- 1 end connects to collecting duct
- 1 end connects to the blood
The collecting ducts act as the branches of the tree which all drain into the ureter
The kidney rises as a result of what interaction?
Reciprocal inductive interactions between
- The small outpocketing of an intermediate mesodermal structure - ureteric bud (epithelial)
- The adjacent mesenchyme - metanephric mesenchyme
What is metanephros?
The formation of definitive kidney
The branching morphogenesis of the ureteric bud is governed by signals from?
The metanephric mesenchyme
Branching morphogenesis of the ureteric bud method
- Signal from mesenchyme causes proliferation and outgrowth of bud tip cells
- GDNF signal binds to RET receptor tyrosine kinase on bud tip cells - Signal transduction pathway activated
- Causes proliferation, migration and outgrowth - Central leading-edge tip cell arrests its proliferation, resulting in a flattening of the bud
- See the highest concentration of GDNF - Lateral tip cells continue to proliferate, resulting in formation of cleft and two tips - branches
- See lower concentrations of GDNF - Lateral tip cells still surrounded by mesenchyme so process repeats
Where do the two signals involved in branching morphogenesis in the ureteric bud come from?
First signals come from a mesenchyme tissue
Then signals from within the epithelial ureteric bud act locally to govern gene expression
Signals coming from the epithelial ureteric bud lead to changes in what?
Lead to change in transcription factor gene expression that autonomously lead to changes in
- Cell migration
- Cell proliferation
- Cell adhesion
- Cell shape
- ECM remodelling
The repeated process in the ureteric bud results in the formation of multiple branches that form?
Go on to differentiate into multiple collecting ducts of each kidney
At the same time collecting ducts are forming what else is formed via reciprocal induction interaction?
Ureteric bud signals to local parts of metanephric mesenchyme
Induces them to form definitive nephric tubules
Induces local nephrogenic mesenchyme to condense around the bud
- Undergo mesenchymal-to-epithelial cell transition
- Form renal epithelium and then renal vesicles
How was renal vesicles formed?
Formed by transcription factors induced in renal epithelium that cause cell-shape changes
What does a renal vesicle go on to form?
A nephron
What shape is a renal vesicle?
S-shaped body which is polarised
What does the proximal end of the renal vesicle do?
Fuse with the bud
Provide local signals for angiogenesis – so capillaries form
What does the distal end of the renal vesicle do?
Attract endothelial capillaries
Fuses with collecting duct by selective apoptosis
How do we study changes in the ureteric bud in real time?
Use transgenic animals, organ cultures and sophisticated imaging
Cloned promoter that normally drives a gene only expressed in the ureteric bud upstream of GFP
- Transgenic animal then contains a ureteric bud that expresses GFP
- Allows studying of branching
What do kidneys form from?
Kidneys form from a mesodermal line of cells - intermediate mesoderm
- Cells extend along the whole of the posterior body
How were the molecular mechanisms of lung morphogenesis discovered?
Through analysis of Drosophila tracheal development
Conserved molecular mechanism for the breathing apparatus
The role of FGF10 and its inhibitor Sprouty
What two tissues are lungs derived from?
Endoderm
Mesoderm
What does lung endoderm give rise to?
Will give rise to epithelial lining of trachea, larynx, bronchi, alveoli
Occurs through branching morphogenesis
What does lung mesoderm give rise to?
Will gives rise to cartilage, muscle and connective tissue
Where do the trachea, bronchi, bronchioles and alveoli come from?
All arise from a bud - respiratory diverticulum
Tip of the respiratory diverticulum then begins to undergo branching morphogenesis
In humans the lung buds form during which week?
4th week
How does the respiratory diverticulum divide?
Respiratory diverticulum is composed of endothelial epithelial cells
Its outgrowth is dependent on signals from adjacent mesoderm/mesenchyme
Lung buds then undergo further branching
A sac of mesoderm surrounds each lung bud
Why is branching limited to the tips in the lungs method
- Endothelial epithelial cells respond to the secretion of FGF from nearby mesenchyme
- Respond by bud formation and extension towards FGF source
- Exposure of tip cells to high FGF concentrations induces expression of secondary genes in the tip
o Including genes that code for – BMP4, Shh and Sprouty 2
o Turning tips of bronchial branches into signaling centers - BMP4 is expressed at highest levels in leading edge tip cells
- It autonomously inhibits epithelial cell proliferation limiting branch extension - flattening the bud
- At the same time, Shh expressed by tip cells diffuses to the mesenchyme
- It inhibits FGF10 expression in the mesenchyme nearest the tip
- This splits FGF10 expression promoting the next round of branching
- Sprouty limits the action of Fgf10 so that branching is restricted to the tip of the branch
How does sprout act through a negative feedback loop?
FGF10 induces expression of genes that direct growth and proliferation
Over a longer time FGF induces expression Sprouty
- Sprouty inhibits FGF signalling
A signal induces its own inhibitor, to limit the time of its own action
What increases in size and number after birth?
Respiratory bronchioles and alveoli continue to increase in number after birth
Only 1/6 of adult alveoli are present at birth
