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Principles of Developmental Biology > Lecture 16- Branching morphogenesis in organs > Flashcards

Lecture 16- Branching morphogenesis in organs Flashcards

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1
Q

Why is branching morphogenesis essential?

A

Where there is a need for a high surface area to volume in order to maximise the efficiency of gas, fluid or solute exchange, secretion or excretion

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2
Q

Give examples of organs where branching morphogenesis occurs

A

Lungs, ureteric bud, salivary glands, prostate, mammary glands and pancreas

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3
Q

What does lung branching morphogenesis create and facilitate?

A

Creates a hight SA:V ratio which facilitates efficient respiratory gas exchange

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4
Q

What is the epithelial component of the kidney?

A

Ureteric bud

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5
Q

What does kidney branching morphogenesis create and facilitate?

A

Creates a dense 3D network of epithelial tubules that maximise the speed and efficiency of the filtration process

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6
Q

What does mammary gland branching morphogenesis create and facilitate?

A

Creates a dense network of epithelial secretory ducts for the production and secretion of milk

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7
Q

What does tracheal system branching morphogenesis create and facilitate in the Drosophila?

A

Creates a hight SA:V ratio which facilitates efficient respiratory gas exchange

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8
Q

Describe the the development of the Drosophila tracheal system

A
  1. The tracheal system develops from segmental pairs of thickened embryonic ectodermal epithelium known as tracheal placodes
  2. The placodes invaginate and then cells proliferate to form hollow sacs of ~80 cells
  3. Some cells in the sac develop filopodia, which then become migratory and create protruding fingers of epithelium that develop into the tracheal tubules
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9
Q

What 2 molecules interact to drive branching of the tracheal epithelium and unicellular branching of the cell tips to enable to outgrowth of the tracheal tubules in Drosophila?

A

Interactions between chemoattractant Branchless protein secreted by epidermal cells and membrane-bound Breathless protein on tracheal epithelial cells

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10
Q

How to branchless protein and breathless receptor interact for the outgrowth of tracheal tubules in the Drosophila?

A
  1. Branchless protein induces branching via activation of Breathless receptor in leader cells
  2. Only Breathless expressing leader cells exposed to highest levels of Branchless protein can form terminal unicellular secondary branches
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11
Q

What have immunohistochemistry studies concluded about branchless for tracheal branching in Drosophila?

A
  • Have shown branchless is necessary for tracheal branching morphogenesis in Drosophila embryos
  • And over-expression of Branchless is sufficient to induce extra tracheal branches in transgenic Drosophila embryos
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12
Q

What 2 cell movements result in tracheal branching morphogenesis in Drosophila?

A

Collective cell migration and cell intercalation

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13
Q

Describe the molecular process of branching in the Drosophila tracheal system

A
  1. Some of the cells in the sac that are exposed to Branchless develop filopodia, and they then become migratory
  2. The migratory cells move towards extracellular sources of Branchless, pulling an elongating tube of cells behind them as a collective
  3. The collective is then extended by a process of cell intercalation and remodeling of cell junctions
  4. Further remodeling of cell junctions and intercalation enables branching from the tracheal sac, giving rise to branches comprising columns of single cells stacked upon top of one another, wrapped around the tubule lumen
  5. The branching pattern is determined by the distribution of Branchless/FGF ligand, secreted by epidermal cells
  6. Sprouty is expressed by the tracheal epithelial cells. Sprouty protein acts in the cytoplasm of cells in which it is expressed to inhibit Breathless
  7. Sprouty inhibits further branching by blocking Breathless signaling in those cells that experience less Branchless activity than the Leader cells, preventing additional branches from forming in the more proximal regions of the tracheal tubules
  8. Leader cells are still responsive to Branchless and they undergo terminal branching by unicellular sprouting, which is also laterally inhibited in cells underneath the Leader cells by Notch-Delta interactions
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14
Q

How does branching compare in Sprouty mutant larvae compared to wild type and what can be concluded from this?

A

Sprouty mutant larvae have many more secondary tubule branches than wild-type larvae

Sprouty gene is required to limit tracheal branching in Drosophila embryo

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15
Q

What does the intermediate mesoderm give rise to?

A

Ureteric bud epithelium and metanephrogenic mesenchyme of the kidneys and gonads

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16
Q

Which gene is expressed in the specification of the intermediate mesoderm?

A

Pax2 gene

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17
Q

What are the 3 major phases of kidney development in mammals?

A
  1. Formation of the Pronephros
  2. Formation of the Mesonephros
  3. Formation of the Metanephros
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18
Q

Describe how the pronephros is formed in the kidney

A
  1. The pronephros is a transient structure that is induced from the nephrogenic mesenchyme by the nephric duct as it migrates posteriorly
  2. The initial kidney, functional in fish and amphibians, not in amniotes
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19
Q

Describe how the mesonephros is formed in the kidney

A
  1. As the pronephric tubules degenerate, the nephric duct induces more kidney tubules in the adjacent mesenchyme, which together make up the mesonephros
  2. In humans about 30 mesonephric tubules form and then they degenerate
  3. Functional in fish and birds, but a transitional non-functional structure in mammals
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20
Q

Describe how the metanephros is formed in the kidney

A
  1. Occurs when a posteriorly located mass of metanephrogenic mesenchyme induces the formation of a branch in each of the paired nephric ducts called the Ureteric Bud
  2. These ducts will eventually grow out to become the collecting ducts and ureters that transport urine to the bladder
  3. So the first two phases of kidney development involve induction of kidney tubules in mesenchyme by the nephric duct, and the final phase involves induction of the ureteric bud in the nephric duct by nephrogenic mesenchyme
  4. The permanent definitive kidney of amniotes, formed through inductive interactions between nephrogenic mesenchyme and the ureteric bud
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21
Q

The ureteric bud epithelium and the metanephrogenic mesenchyme form due to different levels of what signals?

A

FGF9, RA and Wnt

22
Q

Explain the levels of signalling exposed to the anterior intermediate mesoderm and what this results in the tissue becoming

A

Anterior intermediate mesoderm is exposed to higher levels of Fgf9 and Retinoic Acid for longer and lower levels of Wnt for less time therefore developing into ureteric bud epithelium

23
Q

Explain the levels of signalling exposed to the posterior intermediate mesoderm and what this results in the tissue becoming

A

Posterior intermediate mesoderm is exposed to lower levels of Fgf9 and Retinoic Acid for less time and higher levels of Wnt for longer therefore developing into metanephrogenic mesenchyme

24
Q

What intracellular signalling molecule does the metanephrogenic mesenchyme secrete?

A

GDNF

25
Q

Interactions between what tissues regulate the branching morphogenesis ureteric bud?

A

Between the bud and the surrounding metanephrogenic mesenchyme

26
Q

Describe the initial process of ureteric bud branching morphogenesis regulated by GDNF

A
  1. GDNF binds to its receptor the RET RTK which is expressed on the surface of cells located in the Leading-edge tip of the growing Ureteric Bud
  2. Causes proliferation and outgrowth of RET-receptor+ bud ‘tip cells’
  3. Ureteric Bud tip cells stop proliferating in response to GDNF, and this flattens the top of the bud, whilst bud epithelial cells beneath the tip continue to proliferate
  4. The bud then bulges laterally on both sides, and these lateral cells continue to proliferate, extending the bud laterally and forming a cleft between two tips now extending away from one another
  5. As the RET+ve tip cells move away from one another, they secrete BMP7 and FGF2 to prevent the nearby Metanephrogenic Mesenchyme from entering apoptosis, but mesenchyme near the cleft does not receive these signals and so it enters apoptosis, thus creating two distinct aggregates of mesenchyme surrounding the tips of two branches of ureteric epithelium
  6. The next phase of the branching process can now begin
27
Q

What is observed when a GDNF soaked bead in cultured in a mouse nephrite duct?

A

Induces ectopic ureteric bud, highlighting the inductive properties of GDNF

28
Q

How can pax2 expression in the ureteric bud be visualised?

A

Antibody staining of Pax2

29
Q

How many ureteric bud branches are formed after 4 days?

A

64 branches

30
Q

What drives the repeated rounds of synchronous branching within the ureteric bud?

A

Multiple cycles of reciprocal interactions between ureteric epithelium and metanephrogenic mesenchyme

31
Q

Where is Sprouty1 expressed in the mammalian kidney?

A

Sprouty1 gene is expressed in the branches of the developing mouse ureteric bud and not in the metanephrogenic mesenchyme

32
Q

What signalling inhibitor limits through negative feedback branching morphogenesis in the ureteric bud?

A

Sprouty1

33
Q

What is observed in the ureteric bud when Sprouty1 is mutated?

A

Ureteric bud branches more

34
Q

How does Sprouty1 inhibit branching morphogenesis in the ureteric bud?

A
  • Sprouty proteins act as inhibitors of Receptor Tyrosine Kinases (RTKs)
  • In the mouse ureteric bud, the GDNF Receptor RET is also a Receptor Tyrosine Kinase, and it seems that Sprouty1 inhibits its function, thereby limiting the degree of branching morphogenesis that can be accomplished
35
Q

Outline the steps following the induction of ureteric branching

A
  1. At the tips of the branches, Wnt signals released by ureteric bud epithelium then induce mesenchymal aggregation, cavitation and epithelialization to form the renal tubule and Bowman’s Capsule
  2. The renal tubule and Bowman’s Capsule become fused to the tubule formed from the ureteric bud, which then becomes the collecting duct that connects to the ureter
36
Q

What signals released from the ureteric bud drive MET to form the nephron?

A

Wnt signals

37
Q

Which Wnts and how are they involved in transforming the metanephrogenic mesenchymal aggregates into nephrons?

A
  • Wnt11 and Wnt9b signals produced by the ureteric bud epithelium convert aggregated mesenchyme cells into nephrons and are essential for kidney development
  • Wnt9b, which is expressed in the stalk of the Ureteric Bud
  • Wnt11, which is specifically expressed in the RET-expressing tips of the Ureteric Bud that are associated with the mesenchymal aggregates that will become nephrons
38
Q

What is observed in a Wnt9b mice KO and why is this seen?

A

Wnt9b knockout mice lack kidneys, because the nephrogenic mesenchyme degenerates and consequently no nephrons develop

39
Q

What is the result of GDNF and Wnt signalling?

A

Lead to filling the kidney with nephron-collecting duct units that all connect to the single ureter that exits the kidney

40
Q

What 2 germ layers does the human lung develop from?

A

Endoderm and mesoderm

41
Q

What part of the human lung does the endoderm give rise to?

A

Branching epithelial lining of the trachea, larynx, bronchi, bronchioles and alveoli through the process of branching morphogenesis

42
Q

What part of the human lung does the mesoderm give rise to?

A

Cartilage, muscle and connective tissue. Has little role in branching

43
Q

What is the respiratory diverticulum?

A

A ventral bud of endoderm that gives rise to the trachea, bronchi, bronchioles and alveoli

44
Q

What does the tip of the respiratory diverticulum form?

A

The lung buds

45
Q

What forms from the medial and outer edge of the sac of mesoderm? What is the space between?

A

The medial edge of the sac is the visceral pleura and its outer edge is the parietal pleura. The space in between is the pleural cavity.

46
Q

What drives branching morphogenesis in the lung?

A

Branching morphogenesis is driven by repeated cycles of synchronized epithelial mesenchymal interactions at the tips of the lung bud branches

47
Q

What signalling molecules are involves in the branching morphogenesis of the lung?

A

FGF, Shh and BMP

48
Q

Explain the molecular mechanisms which underpin branching morphogenesis of the lung

A
  1. Patches of FGF10 expression in lung mesenchyme up-regulate FGFR2B expression in nearby lung epithelium, stimulating bud outgrowth towards the FGF10-expressing mesenchyme.
  2. Simultaneously, FGF10 induces Sprouty expression in the bud epithelium, which suppresses proliferation of epithelial cells below the tip that are further away from the mesenchyme than cells at the tip, and therefore experience lower levels of FGF10 signaling than tip cells.
  3. Further outgrowth of the bud is restricted to epithelial cells experiencing the highest levels of FGF10 signaling, i.e. tip cells, causing the tip to bulge out.
  4. Tip cells express and secrete both Shh and BMP4 in response to sustained high levels of FGFR2B activation by FGF10. The tip cells function as a Signaling Centre
  5. Shh acts on overlying mesenchyme to suppress FGF10 expression locally, splitting the domain of FGF10 expression into two domains, separated by a gap. BMP4 acts on tip cells themselves, to stop their proliferation.
  6. Epithelial cells beneath the tip that do not express BMP4 continue to grow out laterally towards the 2 separate sources of FGF10, promoting the next round of branching.
  7. Sprouty continues to limit the action of FGF10 signaling to cells at the tip of the two branches, supporting further rounds of branching morphogenesis.
49
Q

Explain how Sprouty1 and FGF10 act in a negative feedback loop

A

High levels of Sprouty induced by FGF attenuate the ability of a cell to respond to further FGF signals

50
Q

What does the lung epithelium eventually develop into?

A

Alveoli

51
Q

Briefly describe how and why the lung epithelium changes to form the alveoli

A

Changing from a cuboidal to a squamous epithelium, which attracts an extensive capillary network of endothelium that becomes integrated with the alveolar epithelium and so maximises the efficiency of gas exchange by blood cells

Principles of Developmental Biology (16 decks)

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