Lung development and notch signaling

Abstract

The respiratory system is connected to the cardiovascular system physically and physiologically. This chapter overviews the morphogenesis and epithelial development of the lung. The airway branching structure is formed as development progresses and is controlled by reciprocal mesenchymal-epithelial interactions. During the branching process, the distal terminal buds are thought to contain a population of multipotent epithelial progenitors that are more proliferative than proximal cells. This predominant proliferation in the distal tip leads to the lung bud extension toward the distal end. As the bronchial tree extends further, descendants of these multipotent cells give rise to lineage-restricted progenitors in the conducting airways. Notch signaling is used repeatedly to organize three epithelial cell types: Club, ciliated, and neuroendocrine (NE) cells. The Notch-mediated fate selection of Club/ciliated cells and of the size of NE cell clusters is regulated by different mechanisms. The Club/ciliated cell fate decision is mediated exclusively by Notch2 in response to Jag1. In contrast, all three Notch receptors contribute to robustly regulate the NE cell-cluster size. High-resolution whole-mount imaging of the developing lung revealed that the NE cell cluster appears at the stereotypic positions at the bifurcating area of the branching airways. Moreover, the 4D imaging, 3D plus live-imaging, method for developing lung epithelial cells discovered dynamics of NE cell clustering in which NE cells appear at inter-bifurcation area as solitary cells and migrate toward the branching points to form clusters. Further analyses determined that Notch signaling regulates the number of solitary NE cells in a lateral-inhibition fashion.