Bud, branch, breathe! Building a mammalian lung over space and time

Abstract

Many mammalian organs, such as the mammary and lachrymal glands, kidney and lungs develop by the process known as branching morphogenesis. An essential feature of this process is the reciprocal interaction between the inner branched tubular epithelium and the surrounding mesenchyme to optimize the final amount of epithelial tissue that is generated for specific functions. To achieve this expansion the initial epithelial population undergoes repeated rounds of bud formation, branch outgrowth and tip bifurcations, with each repertoire requiring dynamic changes in cell behavior. The process of branching morphogenesis was first studied experimentally by Grobstein and others who showed that the embryonic epithelium did not develop without so-called inductive signals from the mesenchyme. However, it was not known whether this activity was uniformly distributed throughout the mesoderm or localized to specific regions. The mouse lung was seen as a powerful system in which to investigate such questions since its early branching is highly stereotypic, both in vivo and in culture. This advantage was exploited by two young scientists, Alescio and Cassini, who used grafting techniques with explanted embryonic mouse lungs. They showed that mesenchyme from around distal buds could induce ectopic buds in the trachea and other non-branching regions of the epithelium. At the same time, distal regions denuded of their mesoderm failed to develop further. They speculated that inductive factors that promote bud formation and continued outgrowth in competent endoderm are specifically localized within the distal mesenchyme, establishing a conceptual framework for future experimentation. Since then, advances in many areas of biology and bioengineering have enabled the identification of gene regulatory networks, signaling pathways and biomechanical properties that mediate lung branching morphogenesis. However, a quantitative model of how these parameters are coordinated over space and time to control the pattern and scale of branching and the overall size of the lung, still remains elusive.