Fusion of lung lobes and vessels in mouse embryos heterozygous for the forkhead box f1 targeted allele.
Previously, we showed that newborn forkhead box (Fox)f1(+/-) mice with diminished pulmonary FoxF1 levels died of severe lung hemorrhage and exhibited abnormal formation of alveolar sacs and capillaries. Another group recently reported that Foxf1(+/-) mouse embryos displayed a number of organ and skeletal defects including fusion of lung lobes. However, identification of pulmonary genes whose altered expression was associated with the lobular fusion defect in Foxf1(+/-) lungs remains uncharacterized. The present study was conducted to determine the nature of the malformations leading to lung fusions in the FoxF1 embryos and to identify potential signaling pathways influenced by FoxF1 haploinsufficiency. We show that Foxf1(+/-) embryos exhibit defects in formation and branching of primary lung buds, which causes fusion of the right lung lobes and vessels. The severity of the Foxf1(+/-) lung fusions was correlated with decreased levels of FoxF1 mRNA. In situ hybridization studies demonstrated that the defective primary lung-bud development in early Foxf1(+/-) embryos was associated with fewer pulmonary mesenchymal-epithelial interfaces. Defects in branching morphogenesis in the Foxf1(+/-) embryos were associated with altered expression of the fibroblast growth factor-10, bone morphogenetic protein-4, and the Gli3 transcription factor, which are known to influence primary lung-bud development.
Lim
Lorena
L
Department of Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607-7170, USA.
Kalinichenko
Vladimir V
VV
Whitsett
Jeffrey A
JA
Costa
Robert H
RH
D000483:Alleles; D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors / Q000235:genetics; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors; D008168:Lung / Q000196:embryology* / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins; D000072079:Patched Receptors; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D020545:Respiratory Mucosa / Q000166:cytology / Q000196:embryology / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics*; D029867:Xenopus Proteins; D000074290:Zinc Finger Protein Gli3; D001616:beta-Galactosidase / Q000235:genetics
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse; C108003:GLI3 protein, Xenopus; C065683:GLI3 protein, human; C465571:Gli3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000072079:Patched Receptors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D014157:Transcription Factors; D029867:Xenopus Proteins; D000074290:Zinc Finger Protein Gli3; C525812:bmp4 protein, Xenopus; D005346:Fibroblast Growth Factors; D001616:beta-Galactosidase