The molecular basis of lung morphogenesis

To form a diffusible interface large enough to conduct respiratory gas exch ange with the circulation, the lung endoderm undergoes extensive branching morphogenesis and alveolization, coupled with angiogenesis and vasculogenes is. It is becoming clear that many of the key factors determining the proce ss of branching morphogenesis, particularly of the respiratory organs, are highly conserved through evolution. Synthesis of information from null muta tions in Drosophila and mouse indicates that members of the sonic hedgehog/ patched/ smoothened/GliF/FGF/FGFR/sprouty pathway are functionally conserve d and extremely important in determining respiratory organogenesis through mesenchymal-epithelial inductive signaling, which induces epithelial prolif eration, chemotaxis and organ-specific gene expression. Transcriptional fac tors including Nkx2.1, HNF family forkhead homologues, GATA family zinc fin ger factors, pou and hox, helix-loop-helix (HLH) factors, Id factors, gluco corticoid and retinoic acid receptors mediate and integrate the development al genetic instruction of lung morphogenesis and cell lineage determination . Signaling by the IGF, EGF and TGF-beta/BMP pathways. extracellular matrix components and integrin signaling pathways also directs lung morphogenesis as well as proximo-distal lung epithelial cell lineage differentiation Sol uble factors secreted by lung mesenchyme comprise a 'compleat' inducer of l ung morphogenesis. In general, peptide growth factors signaling through cog nate receptors with tyrosine kinase intracellular signaling domains such as FGFR, EGFR, IGFR, PDGFR and c-met stimulate lung morphogenesis. On the oth er hand, cognate receptors with serine/threonine kinase intracellular signa ling domains, such as the TGF-P receptor family are inhibitory, although BM P I and BMPR also play key inductive roles. Pulmonary neuroendocrine cells differentiate earliest in gestation From among multipotential lung epitheli al cells. MASH 1 null mutant mice do not develop PNE cells. Proximal and di stal airway epithelial phenotypes differentiate under distinct transcriptio nal control mechanisms. It is becoming clear that angiogenesis and vasculog enesis of the pulmonary circulation and capillary network are closely linke d with and may be necessary for lung epithelial morphogenesis. Like epithel ial morphogenesis, pulmonary vascularization is subject to a fine balance b etween positive and negative factors. Angiogenic and vasculogenic factors i nclude VEGF, which signals through cognate receptors Ak and fit, while nove l anti-angiogenic factors include EMAP II. (C) 2000 Elsevier Science Irelan d Ltd. All rights reserved.