PMID- 10457010 OWN - NLM STAT- MEDLINE DCOM- 19991021 LR - 20220215 IS - 0950-1991 (Print) IS - 0950-1991 (Linking) VI - 126 IP - 18 DP - 1999 Sep TI - Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development. PG - 4005-15 AB - In the mature mouse lung, the proximal-distal (P-D) axis is delineated by two distinct epithelial subpopulations: the proximal bronchiolar epithelium and the distal respiratory epithelium. Little is known about the signaling molecules that pattern the lung along the P-D axis. One candidate is Bone Morphogenetic Protein 4 (Bmp4), which is expressed in a dynamic pattern in the epithelial cells in the tips of growing lung buds. Previous studies in which Bmp4 was overexpressed in the lung endoderm (Bellusci, S., Henderson, R., Winnier, G., Oikawa, T. and Hogan, B. L. M. (1996) Development 122, 1693-1702) suggested that this factor plays an important role in lung morphogenesis. To further investigate this question, two complementary approaches were utilized to inhibit Bmp signaling in vivo. The Bmp antagonist Xnoggin and, independently, a dominant negative Bmp receptor (dnAlk6), were overexpressed using the surfactant protein C (Sp-C) promoter/enhancer. Inhibiting Bmp signaling results in a severe reduction in distal epithelial cell types and a concurrent increase in proximal cell types, as indicated by morphology and expression of marker genes, including the proximally expressed hepatocyte nuclear factor/forkhead homologue 4 (Hfh4) and Clara cell marker CC10, and the distal marker Sp-C. In addition, electron microscopy demonstrates the presence of ciliated cells, a proximal cell type, in the most peripheral regions of the transgenic lungs. We propose a model in which Bmp4 is a component of an apical signaling center controlling P-D patterning. Endodermal cells at the periphery of the lung, which are exposed to high levels of Bmp4, maintain or adopt a distal character, while cells receiving little or no Bmp4 signal initiate a proximal differentiation program. FAU - Weaver, M AU - Weaver M AD - Howard Hughes Medical Institute, Department of Cell Biology, Nashville, TN, USA. FAU - Yingling, J M AU - Yingling JM FAU - Dunn, N R AU - Dunn NR FAU - Bellusci, S AU - Bellusci S FAU - Hogan, B L AU - Hogan BL LA - eng GR - HD28955/HD/NICHD NIH HHS/United States GR - T32-HD07502/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - England TA - Development JT - Development (Cambridge, England) JID - 8701744 RN - 0 (Bmp4 protein, mouse) RN - 0 (Bone Morphogenetic Protein 4) RN - 0 (Bone Morphogenetic Proteins) RN - 0 (Carrier Proteins) RN - 0 (Fibroblast Growth Factor 10) RN - 0 (Hedgehog Proteins) RN - 0 (Proteins) RN - 0 (Proteolipids) RN - 0 (Pulmonary Surfactants) RN - 0 (Receptors, Growth Factor) RN - 0 (Trans-Activators) RN - 148294-77-3 (noggin protein) RN - 62031-54-3 (Fibroblast Growth Factors) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.30 (Bone Morphogenetic Protein Receptors, Type I) SB - IM MH - Animals MH - Bone Morphogenetic Protein 4 MH - Bone Morphogenetic Protein Receptors, Type I MH - Bone Morphogenetic Proteins/*genetics/*metabolism MH - Carrier Proteins MH - Cell Differentiation/genetics MH - Endoderm/*metabolism MH - Fibroblast Growth Factor 10 MH - Fibroblast Growth Factors/genetics/metabolism MH - *Gene Expression Regulation, Developmental MH - Hedgehog Proteins MH - Lung/abnormalities/*embryology/ultrastructure MH - Mesoderm MH - Mice MH - Mice, Inbred ICR MH - Mice, Transgenic MH - Microscopy MH - Microscopy, Electron MH - Protein Serine-Threonine Kinases/genetics/metabolism MH - Proteins/genetics/metabolism MH - Proteolipids/genetics MH - Pulmonary Surfactants/genetics MH - Receptors, Growth Factor/genetics/metabolism MH - Signal Transduction MH - *Trans-Activators MH - Transgenes EDAT- 1999/08/24 00:00 MHDA- 1999/08/24 00:01 CRDT- 1999/08/24 00:00 PHST- 1999/08/24 00:00 [pubmed] PHST- 1999/08/24 00:01 [medline] PHST- 1999/08/24 00:00 [entrez] AID - 10.1242/dev.126.18.4005 [doi] PST - ppublish SO - Development. 1999 Sep;126(18):4005-15. doi: 10.1242/dev.126.18.4005.