Lung Development

Abstract

Early respiratory development begins with the specification of the lung cell fate, followed by the emergence of lung buds from the ventral foregut endoderm. The respiratory tree is then elaborated through branching morphogenesis, and proliferation and differentiation of specialised cell types along the proximal–distal axis produces airways and alveoli, respectively. Lung development is orchestrated through crosstalk between the epithelium and the mesenchyme; morphogenesis and differentiation of the lung relies on diffusible signalling molecules that cross tissue layers to activate a complex network of transcription factors to drive development. Significant progress has been made in understanding the molecular regulation of lung morphogenesis through paracrine signalling pathways and transcription factors essential for lung development.

Key Concepts

  • Following specification of respiratory progenitor cells that are committed to the respiratory lineage, the lung buds emerge from the ventral foregut endoderm and subsequently elaborate the pulmonary tree through branching morphogenesis.

  • Reciprocal interactions between the epithelium and the mesenchyme govern lung organogenesis and are mediated by diffusible factors.

  • Critical signalling pathways known to be involved in lung development include Fgfs, Shh, Wnts, RA and TGF‐β superfamily. These factors are diffusible and act as means of communication and instruction between the tissue layers to drive development.

  • The lung comprises specialised cell types that function to protect the lung, secrete surfactant or allow for gas exchange.

Keywords: lung; tissue interactions; branching morphogenesis; growth factors; transcription factors; signalling pathways

Figure 1. Timeline of key events during lung development in the human and mouse. The five stages of lung development as they occur throughout gestation, and their duration, are highlighted. Notably, human gestation is measured in weeks, whereas mouse gestation is measured in days. E, embryonic day; w, weeks; m, months; PN, postnatal.
Figure 2. Morphological stages of lung development in the mouse. (a, b) Whole‐mount immunohistochemistry depicting early lung morphogenesis. (a) Lung buds emerge from the ventral foregut endoderm at E9.5 (Lg = lung). The thyroid is also visible at this stage (Th = thyroid). (b) By E12.5, the lung epithelium has begun to undergo branching morphogenesis and the vasculature develops in parallel with the epithelium. (c–f) Immunohistochemistry depicting the structural changes from early to late lung development. (c) Section of an E14.5 lung showing the proximal–distal polarity of the lung epithelium, with the more proximal conducting airways surrounded by smooth muscle (arrow), whereas the terminal bronchioles (asterisk) branch and form the distal structures that will eventually become the acini in the adult. The mesenchyme is relatively thick at this stage. (d) E16.5 lung section demonstrating the appearance of epithelial acini, as well as increased vasculature during this stage. Smooth muscle surrounds the airways (arrow) and vessels (arrowheads). (e) By E18.5, the type I cells and capillaries have come together to form the thin air–blood interface necessary for gas exchange. CCSP positive ciliated cells line the proximal epithelium, whereas distal type II cells express SP‐C. (f) Postnatal day 14 lungs. Septation of the alveoli increases the surface area of the lung to allow for sufficient gas exchange. Images (c–f) are all at the same magnification. (a–d) The early lung marker Nkx2.1 marks the epithelium (shown in green), E‐cadherin (E‐cad) outlines the foregut endoderm in blue, smooth muscle cells are depicted in magenta with an antibody against α‐smooth muscle actin and the endothelial cells are depicted in red as marked by endomucin expression. (e, f) Proximal airways are depicted with the ciliated cell marker CCSP in magenta, whereas distal epithelial type II cells are visualised by SP‐C expression in green. Endomucin again marks the endothelial cells in red.
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Further Reading

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Shannon JM and Hyatt BA (2004) Epithelial‐mesenchymal interactions in the developing lung. Annual Review of Physiology 66: 625–645.

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Havrilak, Jamie A, and Shannon, John M(Jan 2015) Lung Development. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0003307.pub2]