Classical experiments in embryology have shown that normal growth, morphogenetic patterning, and cellular differentiation in the developing lung depend on interactive signaling between the endodermal epithelium and mesenchyme derived from splanchnic mesoderm. These interactions are mediated by a myriad of diffusible factors that are precisely regulated in their temporal and spatial expression. In this review we first describe factors regulating formation of the embryonic foregut. We then discuss the experiments demonstrating the importance of tissue interactions in lung patterning and differentiation. Finally, we detail the roles that a few key signaling systems-fibroblast growth factors and their receptors, sonic hedgehog and Gli genes, Wnt genes and beta-catenin, and BMP4-play as mediators of epithelial-mesenchymal interactions in the developing lung.

Pulmonary surfactant is a complex of lipids and proteins produced and secreted by alveolar type II cells that provides the low surface tension at the air-liquid interface. The phospholipid most responsible for providing the low surface tension in the lung is dipalmitoylphosphatidylcholine. Dipalmitoylphosphatidylcholine is synthesized in large part by phosphatidylcholine (PC) remodeling, and a lysophosphatidylcholine (lysoPC) acyltransferase is thought to play a critical role in its synthesis. However, this acyltransferase has not yet been identified. We have cloned full-length rat and mouse cDNAs coding for a lysoPC acyltransferase (LPCAT). LPCAT encodes a 535-aa protein of Ϸ59 kDa that contains a transmembrane domain and a putative acyltransferase domain. When transfected into COS-7 cells and HEK293 cells, LPCAT significantly increased lysoPC acyltransferase activity. LPCAT preferred lysoPC as a substrate over lysoPA, lysoPI, lysoPS, lysoPE, or lysoPG and prefers palmitoyl-CoA to oleoyl-CoA as the acyl donor. This LPCAT was preferentially expressed in the lung, specifically within alveolar type II cells. Expression in the fetal lung and in rat type II cells correlated with the expression of the surfactant proteins. LPCAT expression in fetal lung explants was sensitive to dexamethasone and FGFs. KGF was a potent stimulator of LPCAT expression in cultured adult type II cells. We hypothesize that LPCAT plays a critical role in regulating surfactant phospholipid biosynthesis and suggest that understanding the regulation of LPCAT will offer important insight into surfactant phospholipid biosynthesis.biochemistry ͉ lung ͉ surfactant ͉ phosphatidylcholine

The asymmetries of internal organs are consistently oriented along the left-right axis in all vertebrates, and perturbations of left-right orientation lead to significant congenital disease. We propose a model in which a "left-right coordinator" interacts with the Spemann organizer to coordinate the evolutionarily conserved three-dimensional asymmetries in the embryo. The Vg1 cell-signaling pathway plays a central role in left-right coordinator function. Antagonists of Vg1 alter left-right development; antagonists of other members of the TGFbeta family do not. Cell-lineage directed expression of Vg1 protein can fully invert the left-right axis (situs inversus), can randomize left-right asymmetries, or can "rescue" a perturbed left-right axis in conjoined twins to normal orientation (situs solitus), indicating that Vg1 can mimic left-right coordinator activity. These are the first molecular manipulations in any vertebrate by which the left-right axis can be reliably controlled.

In the development of the three-dimensional vertebrate body plan, the left-right axis is linked to the dorsoventral and anterioposterior axes. In humans, altered left-right development results in severe cardiovascular and visceral abnormalities in individuals and in conjoined twins. Although zygotically transcribed genes that are asymmetrically expressed have been identified, the mechanism by which left-right asymmetries are established during embryogenesis is unknown. Here we show that the Xenopus maternal gene Vg1, a member of the TGF-beta family of cell-signalling molecules which are implicated in dorsoanterior development, initiates left-right axis formation. Altered expression of Vg1 on the right side of 16-cell embryos or disruption of endogenous Vg1 signalling on the left side randomizes cardiac and visceral left-right orientation and alters expression of Xnr-1, a nodal-related molecular marker for left-right development. Furthermore, the orientation of the left-right axis in conjoined twins is dependent upon which cell-signalling molecule initiated twin formation and on whether the secondary axis is on the left or right side of the primary embryonic axis, implicating a molecular pathway leading to the formation of conjoined twins.

The induction, growth, and differentiation of epithelial lung buds are regulated by the interaction of signals between the lung epithelium and its surrounding mesenchyme. Fibroblast growth factor-10 (FGF-10), which is expressed in the mesenchyme near the distal tips, and bone morphogenetic protein 4 (BMP4), which is expressed in the most distal regions of the epithelium, are important molecules in lung morphogenesis. In the present study, we used two in vitro systems to examine the induction, growth, and differentiation of lung epithelium. Transfilter cultures were used to determine the effect of diffusible factors from the distal lung mesenchyme (LgM) on epithelial branching, and FGF-10 bead cultures were used to ascertain the effect of a high local concentration of a single diffusible molecule on the epithelium. Embryonic tracheal epithelium (TrE) was induced to grow in both culture systems and to express the distal epithelial marker surfactant protein C at the tips nearest the diffusible protein source. TrE cultured on the opposite side of a filter to LgM branched in a pattern resembling intact lungs, whereas TrE cultured in apposition to an FGF-10 bead resembled a single elongating epithelial bud. Examination of the role of BMP4 on lung bud morphogenesis revealed that BMP4 signaling suppressed expression of the proximal epithelial genes Ccsp and Foxj1 in both types of culture and upregulated the expression of Sprouty 2 in TrE cultured with an FGF-10 bead. Antagonizing BMP signaling with Noggin, however, increased expression of both Ccsp and Foxj1.