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PMID:11493558

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Citation

Mahlapuu, M, Enerbäck, S and Carlsson, P (2001) Haploinsufficiency of the forkhead gene Foxf1, a target for sonic hedgehog signaling, causes lung and foregut malformations. Development 128:2397-406

Abstract

The murine Foxf1 gene, encoding a forkhead - or winged helix - transcription factor, is expressed in splanchnic mesenchyme during organogenesis. The concentration of expression to subepithelial mesenchyme suggested that Foxf1 is activated by paracrine signals from endodermal epithelia. Homozygous Foxf1-null mice die before embryonic day 10, owing to defects in extra-embryonic mesoderm, and do not provide any information about the role of Foxf1 in morphogenesis of endodermally derived organs. We show that, on CD1 genetic background, Foxf1 heterozygote perinatal mortality is around 90%. The haploinsufficiency causes a variable phenotype that includes lung immaturity and hypoplasia, fusion of right lung lobes, narrowing of esophagus and trachea, esophageal atresia and tracheo-esophageal fistula. Similar malformations are observed in mutants that are defective in the sonic hedgehog (Shh) signaling pathway, and we show that exogenous Shh activates transcription of Foxf1 in developing lung. Foxf1 mRNA is absent in the lungs, foregut and sclerotomes of Shh(-/-) embryos, but persists in tissues where indian hedgehog (Ihh) is expressed. In lung organ cultures, activation of Foxf1 by Shh is counteracted by bone morphogenetic protein 4 (BMP4). Fibroblast growth factor (FGF) 10 and FGF7 both decrease Foxf1 expression and we speculate that this is mediated by transcriptional activation of epithelial Bmp4 (in the case of FGF10) and by inhibition of Shh expression for FGF7.

Links

PubMed

Keywords

Animals; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins/metabolism; COS Cells; Cell Line; Cercopithecus aethiops; DNA-Binding Proteins/genetics; DNA-Binding Proteins/physiology; Down-Regulation; Female; Forkhead Transcription Factors; Gene Expression Regulation, Developmental; Hedgehog Proteins; Heterozygote; Humans; Intestine, Small/embryology; Lung/embryology; Male; Mice; Mice, Inbred C57BL; Morphogenesis/physiology; Signal Transduction; Trans-Activators/genetics; Trans-Activators/metabolism; Trans-Activators/physiology; Transcription Factors/genetics; Transcription Factors/physiology; Transcriptional Activation

Significance

Annotations

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

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0030324: lung development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

  • results_in_development_of:(EMAPA:16728)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0007368: determination of left/right symmetry

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(EMAPA:16728)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0060463: lung lobe morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0060461: right lung morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0060441: epithelial tube branching involved in lung morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

  • occurs_in:(EMAPA:17661)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0060438: trachea development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

  • results_in_development_of:(EMAPA:16853)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0060425: lung morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0048286: lung alveolus development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

  • results_in_development_of:(EMAPA:19001)|results_in_development_of:(EMAPA:19005)

Seeded From UniProt

complete

MOUSE:PTC1

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(EMAPA:16728)

Seeded From UniProt

complete

MOUSE:SHH

acts_upstream_of_or_within

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

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(MGI:MGI:1347470)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0007368: determination of left/right symmetry

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_participant:(EMAPA:16039)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0007498: mesoderm development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0030324: lung development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

results_in_development_of:(EMAPA:16728)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0048617: embryonic foregut morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0051145: smooth muscle cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0048286: lung alveolus development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

results_in_development_of:(EMAPA:19001)|results_in_development_of:(EMAPA:19005)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0060463: lung lobe morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

has_participant:(EMAPA:17661)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0060461: right lung morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

has_participant:(EMAPA:17661)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0060441: epithelial tube branching involved in lung morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

occurs_in:(EMAPA:17661)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0060438: trachea development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

results_in_development_of:(EMAPA:16853)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0060425: lung morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

has_participant:(EMAPA:16728)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(EMAPA:16728)

Seeded From UniProt

complete

MOUSE:FOXF1

acts_upstream_of_or_within

GO:0001701: in utero embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1929432

P

Seeded From UniProt

complete

MOUSE:SHH

acts_upstream_of_or_within

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

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(MGI:MGI:1347470)

Seeded From UniProt

complete

MOUSE:PTC1

acts_upstream_of_or_within

GO:0007224: smoothened signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(EMAPA:16728)

Seeded From UniProt

complete

MOUSE:BMP4

acts_upstream_of_or_within

GO:0010629: negative regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FGF7

acts_upstream_of_or_within

GO:0050679: positive regulation of epithelial cell proliferation

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P21781

P

Seeded From UniProt

complete


See also

References

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