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PMID:16989802

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Citation

De Langhe, SP, Carraro, G, Warburton, D, Hajihosseini, MK and Bellusci, S (2006) Levels of mesenchymal FGFR2 signaling modulate smooth muscle progenitor cell commitment in the lung. Dev. Biol. 299:52-62

Abstract

Fibroblast growth factor (FGF) signaling has been shown to regulate lung epithelial development but its influence on mesenchymal differentiation has been poorly investigated. To study the role of mesenchymal FGF signaling in the differentiation of the mesenchyme and its impact on epithelial morphogenesis, we took advantage of Fgfr2c(+/Delta) mice, which due to a splicing switch express Fgfr2b in mesenchymal tissues and manifest Apert syndrome-like phenotypes. Using a set of in vivo and in vitro studies, we show that an autocrine FGF10-FGFR2b signaling loop is established in the mutant lung mesenchyme, which has several consequences. It prevents the entry of the smooth muscle progenitors into the smooth muscle cell (SMC) lineage and results in reduced fibronectin and elastin deposition. Levels of Fgf10 expression are raised within the mutant mesenchyme itself. Epithelial branching as well as epithelial levels of FGF and canonical Wnt signaling is dramatically reduced. These defects result in arrested development of terminal airways and an "emphysema like" phenotype in postnatal lungs. Our work unravels part of the complex interactions that govern normal lung development and may be pertinent to understanding the basis of respiratory defects in Apert syndrome.

Links

PubMed Online version:10.1016/j.ydbio.2006.07.001

Keywords

Animals; Animals, Newborn; Autocrine Communication/physiology; Cell Differentiation/physiology; Epithelial Cells/cytology; Epithelial Cells/metabolism; Fibroblast Growth Factor 10/deficiency; Fibroblast Growth Factor 10/genetics; Fibronectins/metabolism; Gene Expression Regulation, Developmental; Heterozygote; Lung/cytology; Lung/embryology; Mesoderm/metabolism; Mice; Myocytes, Smooth Muscle/cytology; Phenotype; RNA, Messenger/genetics; RNA, Messenger/metabolism; Receptor, Fibroblast Growth Factor, Type 2/genetics; Receptor, Fibroblast Growth Factor, Type 2/metabolism; Signal Transduction; Stem Cells/cytology; Wnt Proteins/metabolism

Significance

Annotations

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

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0045165: cell fate commitment

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0048286: lung alveolus development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

  • results_in_development_of:(EMAPA:32692)

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0008543: fibroblast growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2153817

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0060463: lung lobe morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

  • has_participant:(EMAPA:17661)

Seeded From UniProt

complete

MOUSE:ACTA

part_of

GO:0005856: cytoskeleton

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:16728)

Seeded From UniProt

complete

MOUSE:FGF10

acts_upstream_of_or_within

GO:0060915: mesenchymal cell differentiation involved in lung development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:95523

P

Seeded From UniProt

complete

MOUSE:FGF10

acts_upstream_of_or_within

GO:0048286: lung alveolus development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:95523

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0035264: multicellular organism growth

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0040036: regulation of fibroblast growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2153817

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0070372: regulation of ERK1 and ERK2 cascade

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0060916: mesenchymal cell proliferation involved in lung development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0060915: mesenchymal cell differentiation involved in lung development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1099809

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0030177: positive regulation of Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0060501: positive regulation of epithelial cell proliferation involved in lung morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0060484: lung-associated mesenchyme development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0060463: lung lobe morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

has_participant:(EMAPA:17661)

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0060449: bud elongation involved in lung branching

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0060348: bone development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0051150: regulation of smooth muscle cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0009791: post-embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0010453: regulation of cell fate commitment

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0048286: lung alveolus development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3629660

P

results_in_development_of:(EMAPA:32692)

Seeded From UniProt

complete

MOUSE:FGFR2

acts_upstream_of_or_within

GO:0048286: lung alveolus development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1099809

P

Seeded From UniProt

complete

MOUSE:CTNB1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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