Basic Mechanisms of Lung Development

Studies of the molecular regulation of lung development have reached the log-growth phase. The key questions related to lung development are formidable ones to answer, demanding sophisticated and sensitive molecular tools and the use of many different animal, organ, and cellular experimental models. The eighth Y2K Woods Hole Conference on Lung Cell Biology, organized by faculty of the Pulmonary Center, Boston University School of Medicine, and supported by the Division of Lung Diseases of the National Heart, Lung, and Blood Institute, explored some of the recent research in this basic area of lung cell and molecular biology. Many of the fundamental questions, concepts, and observations about basic developmental processes and lung development have been addressed in recent reviews (1‐10). Fundamental Questions The fundamental questions in lung development are interesting but difficult to answer in specific molecular terms. Many, if not all, of these questions apply to the development of other organs and are not unique to lung development per se or to the mammalian lung. For that reason a number of presentations summarized the current molecular understanding of model systems including chick limb, tracheal system of Drosophila , and organogenesis of the mammalian liver. Other presentations described postnatal development because it is well known that certain changes in lung structure and function, such as alveolization, occur mainly after birth. The key questions discussed at the meeting included these: What directs an area of the foregut to become lung, and what cellular and molecular mechanisms account for initiation of budding to form the lung? What are the positive and negative regulators of branching that result in bronchial tree formation? What signaling pathways are involved, and what target genes are activated or repressed to initiate cell proliferation, differentiation, deposition of matrix, and vasculogenesis of the lung? What are the regulatory events that result in the proximal-to-distal patterns of epithelial differentiation? What genes control airway and alveolar dimensions? How is expression of important lung genes specifically regulated? What are the developmental and adult functions of proteins expressed solely and/or mainly in the lung? How plastic is the phenotype of differentiated lung cells, both in developing and adult lung? It is clear that we have assembled lists of molecules that appear to influence lung development, and other lists describing changes in cellular, molecular, and organ phenotypes due to manipulation of the amount, site, or timing of expression of these molecules. However, we do not understand well—if at all—the integrated regulatory pathways that direct the complex processes that produce this highly patterned, multicellular organ.