Branching morphogenesis in organs (L16) Flashcards
What is branching morphogenesis? Give an example
BRanching morphogenesis is a process that is fundamental to the function of many tissues, where there is a need for a high surface area. E.g. in the lungs, ureteric bud, salivary gland, prostate, mammary gland and pancreas. Lungs have a 3D branching structure with 54611 branches, this gives it a massive surface area.
How do definitive kidneys arise?
They arise as a result of reciprocal inductive interactions between 2 structures (one tissue signals to the second, changing it. Part of the second tissue change allows it to signal back to the first tissue) A small out-pocketing of an intermediate mesodermal structure called the ureteric bud (epithelial) and the adjacent mesenchyme, called the metanephric mesenchyme. It is the interaction between these that form the kidneys.
What are the steps that govern branching morphogenesis of the ureteric bud?
- signals from metanephric mesenchyme cause proliferation and outgrowth of bud ‘tip cells’
- The leading edge tip cells arrest its proliferation, resulting in a flattening of the bud - the cells in the middle see higher levels of the signal, this decreases its proliferation (think like parents encouraging it so much it becomes nagging)
- Lateral tip cells continue to proliferate, resulting in the formation of a cleft and 2 tips
- Lateral tip cells still surrounded by mesenchyme - the process repeats
This repeating results information of multiple branches. These will go on to differentiate into the multiple collecting ducts of each kidney
At the same time, the ureteric bud signals to local parts of the metanephric mesenchyme, inducing these parts to form definitive nephric tubules. The ureteric bid induces local nephrogenic mesenchyme to condense around the bud and undergo a MET and form renal epithelium, then renal vesicles. The renal vesicles then proliferate and differentiate to form a nephron
What is the signal involved in the branching in kidneys
The signal that comes from the mesenchyme is GDNF, and its receptor on the bud is a receptor tyrosine kinase called Ret. GDNF was initially identified as a neurotrophic factor. It acts to promote proliferation, migration and outgrowth. So, changes in TFs intrinsically/autonomously leads to changes in cell behaviour.
How does the ureteric bud cause nephron formation after it has branched?
The ureteric bud signals to local parts of the metanephric mesenchyme, inducing these parts to form definitive nephric tubules. The ureteric bid induces local nephrogenic mesenchyme to condense around the bud and undergo a MET and form renal epithelium, then renal vesicles. The renal vesicles then proliferate and differentiate to form a nephron. Distally, the renal vesicles will fuse with the bud, but proximally they will attract endothelial capillaries. The molecular pathways that determine how the S-shaped body becomes polarised so that its distal and proximal ends have different properties. Proximal ends provide local signals for angiogenesis and distal ends fuse with collecting ducts by selective apoptosis.
How many branches do ureteric buds undergo? How can this be studied?
The ureteric bid undergoes repeated branching morphogenesis. Ultimately, they for 10^6 renal vesicle inducing buds in each kidney. We can study the processes in real time using transgenic animals, organ cultures and sophisticated imaging. Kidneys form from a mesodermal line of cells, called the intermediate mesoderm. This line of cells extends along the whole side of the posterior body (one line per side of the body)
How was the branching morphogenesis of lungs mainly studied?
Through analysis of Drosophila tracheal analysis. It showed the mechanism is conserved from flies to vertebrates like humans - specifically the role of FGF10 and its inhibitor.
What 2 tissues are the lungs derived from?
The mesoderm and endoderm.
The endoderm gives rise to the epithelial lining of trachea, larynx, bronchi, and alveoli, through branching morphogenesis. The mesoderm gives rise to the cartilage of the trachea, muscle and connective tissues.
What bud do the main structures of the lung arise from?
The formation of the trachea, bronchi, bronchioles and alveoli all arise from a bud called the respiratory diverticulum. In humans, the lung buds form during 4th weel. Their outgrowth is dependent on signals from the adjacent mesoderm/mesenchyme.
How does the pleura of the lungs form?
A sac of mesoderm surrounds each lung bud. Its medial edge is the visceral pleura and its outer edge is the parietal pleura (in between is the pleural cavity)
How does branching in the lungs work?
- Endothelial epithelial cells, expressing FGFR (FGF receptor) respond to the secretion of FGF from the mesenchyme nearby. They form buds and extend these buds towards the FGF source. Exposure of the tips to high concentrations of FGF induces the expression of secondary genes in the tip, including genes that code for signals - in particular, BMP4, Shh and sprouty2. Thus turning the tips of the bronchial branches into signalling centres. This ensures that branching is limited to only the tips.
- BMP4 is expressed at highest levels in the leading edge tip cells and autonomously inhibits epithelial cell proliferation limiting branch extension ie. causes flattening of the bid. At the same time, Shh expressed by the tip cells diffuses into the mesenchyme, and 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 sprouty control branching?
Sprouty causes a negative feedback loop. Fgf10 induces expression of genes that direct growth and proliferation. Over a slightly longer time frame, FGF also induces expression of sprouty. SProuty inhibits FGF signalling. The signal is inducing its own inhibitor, controlling its own expression by limiting growth. This acts as a fail-safe system f FGF isn’t limited enough by Shh
How does lung tissue involved in gas exchange develop?
Development of lung tissue involved in air exchange occurs later. Once alveoli are generated, they attract endothelial blood cells, which come into close contact and provide extensive capillary networks required for gas exchange. At birth, respiratory bronchioles and alveoli continue to increase in number (and become more muscular) after birth. Only 1/6th of adult alveoli are present at birth. This is a good example of a protracted developmental event.
