Abstract

Recent studies support a model in which the progeny of SOX9+ epithelial progenitors at the distal tip of lung branches undergo cell allocation and differentiation sequentially along the distal‐to‐proximal axis. Concomitant with the elongation and ramification of lung branches, the descendants of the distal SOX9+ progenitors are distributed proximally, express SOX2, and differentiate into cell types in the conducting airways. Amid subsequent sacculation, the distal SOX9+ progenitors generate alveolar epithelial cells to form alveoli. Sequential cell allocation and differentiation are integrated with the branching process to generate a functional branching organ. This review focuses on the roles of SOX9+ cells as precursors for new branches, as the source of various cell types in the conducting airways, and as progenitors of the alveolar epithelium. All of these processes are controlled by multiple signaling pathways. Many mouse mutants with defective lung branching contain underlying defects in one or more steps of cell allocation and differentiation of SOX9+ progenitors. This model provides a framework to understand the molecular basis of lung phenotypes and to elucidate the molecular mechanisms of lung patterning. It builds a foundation on which comparing and contrasting the mechanisms employed by different branching organs in diverse species can be made.