2017 Group Project 5: Difference between revisions
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- Sox 2 is a Sry related HMG | - Sox 2 is a Sry related HMG | ||
- There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions | - There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions | ||
- Development of a transgenic mice with doxycycline inducible Sox2 expressed in their lung epithelium | - Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium | ||
- Results showed | - Results showed a diminution of branching airways and alveoli bronchiolization | ||
==Abnormal development== | ==Abnormal development== |
Revision as of 09:41, 13 September 2017
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Lungs
An introduction to the lungs...
On this page, we will be exploring the development of the lungs through the stages of embryonic growth.
Lung Anatomy
Lung Histology
Developmental origin overview
Brief overview of development of lung
More detailed overview in lung development stages
The Respiratory Zone
The Terminal Bronchioles
Alveolar ducts
Alveoli
The Conducting Zone
The Lung Development Stages
Developmental timeline
Structure of respiratory network
Physiologically, the organ can be divided into two parts:
The Conducting system – consists of all tubular structures including the larynx, trachea and bronchi. (image)
The Functional unit – An alveolus containing specialised epithelial cells where gas exchange occurs.
By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.
A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view
Developmental signalling processes
The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.
Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:
1. Fibroblast Growth Factor (FGF10) - serves as a signalling cue for epithelium outgrowth in the mesenchyme.
2. Sonic Hedgehog (SHH) - produced in the epitheliumand is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.
3. Heparan Sulfate Glycosaminoglycans (HS-GAG) - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.
Early buds formation is dependent on reciprocal interactions between the lung epithelium and mesenchyme mediated by distinct signalling.
Distal signalling centre is marked by the expression of fibroblast growth factor FGF10 in the mesenchyme. FGF10 signalling serves as cue for epithelium outgrowth.
The Conducting System
Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail. The bronchial tree arises from the sequential use of three simple modes of branching.
These modes include:
1. Domain branching
2. Planar bifurcation
3. Orthogonal bifurcation
Trifurcations have also been observed, however it is not as prevalent.
These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored. For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally. FGF10 appears to drive outgrowth of lung buds, as well as other organs.
With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree. In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.
Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior. The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.
In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process. Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.
- Add image of branching patterns
Alveolus: the functional unit
How the alveoli work. Cell types Maturation and development Surfactant - where cells are derived from (macrophages, type 1 and type 2 pneumocytes) Lungs become fully developed within the mother, however they do not function until birth.
At the end of the conducting system, are sac-like structures known as alveoli, which are assist in gas in exchange.
Current understandings and areas of research
include any relevant articles
Review and research articles
Movies
Animal models
Mouse models
Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Shh, and Wnt.... Sox 2
Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway. (noncanonical/calcium, canonical, noncanonical planar cell polarity)
Wnt7b signaling role in embryonic lung development? (body axis patterning ... cell fate specification, cell proliferataion, cell migration) ... "regulates tube shape and branch-point formation in the lung through control of epithelial cell shape" - Wnt 7b actions have a widespread effect in tissue development & regulation of mesenchymal differentiation as seen in mouse lung development models - Wnt pathway: interaction of the Wnt protein to LRP coreceptor complex to cause the stabilisation and nuclear translocation of beta catenin
Sox 2 - branching morphogenesis and epithelial cell differentiation. - Sox 2 is a Sry related HMG - There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions - Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium - Results showed a diminution of branching airways and alveoli bronchiolization
Abnormal development
Premature Birth
Lobar Emphysema
Congenital Diaphragmatic Hernia
Azygos lobe
Meconium Aspiration Syndrome
Newborn Respiratory Distress Syndrome
Surfactant Metabolism
Bronchopulmonary Dysplasia
Lung Agenesis
Cystic Fibrosis
CHAOS (Congenital High Airway Obstruction Syndrome)
CPAM (Congenital Pulmonary Airway Malformation)
Lung Cardiovasculature
Future questions
Glossary
References
- ↑ Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/