Just as breathing is essential to life, a well-developed lung is needed for getting the oxygen from the air we breathe into the bloodstream. Our lungs are composed of millions of branching airway tubes, which form a bronchial tree that brings inspired air to the terminal gas exchange units called alveoli. Perhaps due to this organ's complexity, the series of developmental events that create lungs were not well understood. However, Ross Metzger and colleagues from Stanford University hypothesized that a simple pattern may underlie this complexity, and decided to examine how airways develop in the lungs of mice.
Lung development cannot be visualized in living embryos, so the authors decided to examine the pattern of airway branching in fixed embryos under the microscope. In doing so, they realized that the bronchial tree contains only three unique types of branching, which they called domain branching, planar bifurcation and orthogonal bifurcation. In domain branching, multiple daughter branches form in rows stemming from a single parent branch, like the rows of bristles on a bottle brush. Planar bifurcation occurs when a parent branch splits into two daughter branches, which can themselves split, and all the branching occurs in a single two-dimensional plane. Orthogonal bifurcation is similar to planar bifurcation, except that each successive split occurs at right angles to the one before it. The highly complex lung is therefore generated by just three simple modes of branching!
The next question was how the developmental sequence of these three types of branching determines the overall lung structure. Metzger and colleagues reconstructed the branching sequence by observing embryos at multiple developmental stages. They found that the three branching modes occurred in a remarkably consistent and stereotyped manner: there were only three specific sequences, each containing seven or more series of branching modes. Domain branching is generally used first in the sequence to create the overall shape of the lungs, followed by planar bifurcation to form the thin edges between different lobes and orthogonal branching to fill the interior.
Because the programme of lung development is simple and stereotyped, this process may be controlled by a relatively small number of genes. As a first step towards finding the genes that control lung development, the authors examined how the development programme is altered in mouse strains with lung defects. Knocking out one gene, called sprouty 2, increased the number of branches within the domains in some regions of the lung, so this gene may normally control domain branching. Disruption of other genes altered the stereotyped branching sequence or had global effects on overall lung design.
The meticulous work of Metzger and colleagues suggests that the complexity of the lung is based on a simple developmental pattern. With this new detailed information, a much better understanding of the molecular and genetic basis for lung structure is within reach. Although much has yet to be discovered,these authors have added a breath of fresh air to the topic of how lungs develop.
