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PMID:8674409

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Citation

Bellusci, S, Henderson, R, Winnier, G, Oikawa, T and Hogan, BL (1996) Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis. Development 122:1693-702

Abstract

Epithelial-mesenchymal interactions are critical for the branching and differentiation of the lung, but the mechanisms involved are still unclear. To investigate this problem in mouse embryonic lung, we have studied the temporal and spatial expression of genes implicated in the morphogenesis of other organs. At 11.5 days p.c., hepatocyte nuclear factor-3beta (Hnf-3beta) is expressed uniformly throughout the epithelium, while Wnt-2 expression is confined to the distal mesenchyme. Sonic hedgehog (Shh) transcripts are found throughout the epithelium, with high levels in the distal tips of the terminal buds, while bone morphogenetic protein-4 (Bmp-4) transcripts are localized at high levels in the distal tips of the epithelium, with lower levels in the adjacent mesenchyme. Epithelial expression is also seen for Bmp-7, but transcripts are less dramatically upregulated at the distal tips. The Type I Bone morphogenetic protein receptor gene (Bmpr/Tfr-11/Brk-1) is expressed at low levels in the epithelium and in the distal mesenchyme. To investigate the role of Bmp-4 in lung development, we have misexpressed the gene throughout the distal epithelium of transgenic lungs using a surfactant protein C enhancer/promoter. From 15.5 days p.c., transgenic lungs are smaller than normal, with grossly distended terminal buds and, at birth, contain large air-filled sacs which do not support normal lung function. Labeling with BrdU reveals an inhibition of epithelia] proliferation in 15.5 days p.c. transgenic lungs. A small but significant stimulation of proliferation of mesenchymal cells is also observed, but this is accompanied by an increase in cell death. In situ hybridization with riboprobes for the proximal airway marker, CC10, and the distal airway marker, SP-C, shows normal differentiation of bronchiolar Clara cells but a reduction in the number of differentiated Type II cells in transgenic lungs. A model is proposed for the role of BMP4 and other signalling molecules in embryonic lung morphogenesis.

Links

PubMed

Keywords

Animals; Base Sequence; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Cell Death; Cell Division; DNA Primers; DNA-Binding Proteins/biosynthesis; Epithelial Cells; Gene Expression; Hedgehog Proteins; Hepatocyte Nuclear Factor 3-beta; Humans; Lung/cytology; Lung/embryology; Lung/ultrastructure; Mesoderm/cytology; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Molecular Sequence Data; Morphogenesis/genetics; Morphogenesis/physiology; Nuclear Proteins/biosynthesis; Protein Biosynthesis; Proteins/genetics; Proteins/physiology; Proteolipids/genetics; Proteolipids/metabolism; Proto-Oncogene Proteins/biosynthesis; Proto-Oncogene Proteins/genetics; Pulmonary Surfactants/genetics; Pulmonary Surfactants/metabolism; Rats; Recombinant Fusion Proteins/genetics; Trans-Activators; Transcription Factors; Transforming Growth Factor beta; Wnt2 Protein

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:BMP4

acts_upstream_of_or_within

GO:0010942: positive regulation of cell death

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

acts_upstream_of_or_within

GO:0009791: post-embryonic development

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

acts_upstream_of_or_within

GO:0060503: bud dilation involved in lung branching

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

acts_upstream_of_or_within

GO:0060502: epithelial cell proliferation involved in lung morphogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

acts_upstream_of_or_within

GO:0060441: epithelial tube branching involved in lung morphogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

acts_upstream_of_or_within

GO:0060438: trachea development

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

acts_upstream_of_or_within

GO:0048286: lung alveolus development

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

acts_upstream_of_or_within

GO:0060433: bronchus development

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

acts_upstream_of_or_within

GO:0060425: lung morphogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BMP4

acts_upstream_of_or_within

GO:0010942: positive regulation of cell death

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12644

P

  • regulates_o_occurs_in:(EMAPA:17654)

Seeded From UniProt

complete

MOUSE:BMP4

acts_upstream_of_or_within

GO:0060438: trachea development

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12644

P

  • results_in_development_of:(EMAPA:16853)

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0009791: post-embryonic development

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0010942: positive regulation of cell death

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0048286: lung alveolus development

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0060425: lung morphogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0060433: bronchus development

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0060438: trachea development

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0060441: epithelial tube branching involved in lung morphogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0060502: epithelial cell proliferation involved in lung morphogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0060503: bud dilation involved in lung branching

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BMP4

acts_upstream_of_or_within

GO:0048286: lung alveolus development

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12644

P

Seeded From UniProt

complete

MOUSE:BMP4

acts_upstream_of_or_within

GO:0009791: post-embryonic development

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12644

P

Seeded From UniProt

complete

MOUSE:BMP4

acts_upstream_of_or_within

GO:0010942: positive regulation of cell death

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12644

P

Seeded From UniProt

complete

MOUSE:BMP4

acts_upstream_of_or_within

GO:0060425: lung morphogenesis

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12644

P

Seeded From UniProt

complete

MOUSE:BMP4

acts_upstream_of_or_within

GO:0060433: bronchus development

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12644

P

Seeded From UniProt

complete

MOUSE:BMP4

acts_upstream_of_or_within

GO:0060438: trachea development

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12644

P

Seeded From UniProt

complete

MOUSE:BMP4

acts_upstream_of_or_within

GO:0060441: epithelial tube branching involved in lung morphogenesis

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12644

P

Seeded From UniProt

complete

MOUSE:BMP4

acts_upstream_of_or_within

GO:0060502: epithelial cell proliferation involved in lung morphogenesis

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12644

P

Seeded From UniProt

complete

MOUSE:BMP4

acts_upstream_of_or_within

GO:0060503: bud dilation involved in lung branching

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12644

P

Seeded From UniProt

complete


See also

References

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