Balancing The Developmental Niches Within The Lung

The capacity to perform gas exchange with the environment is an evolutionary milestone of terrestrial development. The lung has undergone extensive alterations during evolution to acquire a large surface area to efficiently perform gas exchange between the oxygen-rich environment and the cardiovascular system. A process called branching morphogenesis has been used by the respiratory system to elaborate a simple endoderm tube into an extensive arborized organ that interacts closely with the vasculature to generate the proper amount of surface area to efficiently exchange oxygen and carbon dioxide with the cardiovascular system. The molecular mechanisms that regulate branching morphogenesis during lung development have been extensively investigated in the past decade. Many studies have highlighted the distinct morphological and molecular mechanisms that distinguish the structural conducting airways and the distal alveolar airspaces where gas exchange occurs. Despite this, there are still many remaining questions regarding how these distinct spatial units within the lung develop in a coordinated fashion. In the paper by Chang et al. (1), the authors provide a model where the main branching program of the lung airways antagonizes the development of the alveolar unit. Using an elegant series of genetic models in mice, the authors show that a Kras-Sox9 molecular axis provides the necessary spatial information to allow for alveolar development to progress and establish the critical airspaces for gas exchange to occur in the postnatal respiratory system. Such information provides critical insight into congenital lung anomalies that likely involve disruptions in branching and early patterning, including cystic lung diseases. The process of branching morphogenesis is genetically hardwired for at least the first 16 branch generations in the human lung, indicating tight molecular control over the process. Importantly, an extensive epithelial–mesenchymal signaling complex is required for initiating and promoting branch points at precise regions of the forming airway tree. …