Hepatocyte nuclear factor-3beta limits cellular diversity in the developing respiratory epithelium and alters lung morphogenesis in vivo.
Hepatocyte nuclear factor-3beta (HNF-3beta), a nuclear protein of the winged helix family of transcription factors, is known to play a critical role in the formation of the embryonic node, notochord, and foregut endoderm. HNF-3beta influences the expression of a number of target genes in the respiratory epithelium, activating transcription of thyroid transcription factor-1, surfactant protein-B and clara cell secretory protein. In order to discern the role of HNF-3beta in differentiation and gene expression in the lung, HNF-3beta was expressed in developing respiratory epithelial cells of transgenic mice, under the control of the human surfactant protein C gene promoter. Pulmonary abnormalities were observed in the lungs of fetal mice bearing the HNF-3beta transgene. Differentiation of distal respiratory epithelial cells was arrested in the early pseudoglandular stage. Branching morphogenesis and vasculogenesis were markedly disrupted in association with decreased E-cadherin and vascular endothelial growth factor expression. HNF-3beta limits cellular diversity of developing respiratory epithelium and alters lung morphogenesis in vivo, suggesting that precise temporal-spatial regulation of HNF-3beta expression is critical for respiratory epithelial cell differentiation and lung morphogenesis.
Zhou
L
L
Children's Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, Ohio 45229-3039, USA.
Dey
C R
CR
Wert
S E
SE
Yan
C
C
Costa
R H
RH
Whitsett
J A
JA
D000818:Animals; D015820:Cadherins / Q000235:genetics; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology*; D051542:Hepatocyte Nuclear Factor 3-beta; D006801:Humans; D008168:Lung / Q000166:cytology / Q000196:embryology*; D008222:Lymphokines / Q000235:genetics; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D015820:Cadherins; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C496502:FOXA2 protein, human; C496503:Foxa2 protein, mouse; C496504:Foxa2 protein, rat; D008222:Lymphokines; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051542:Hepatocyte Nuclear Factor 3-beta