Foxf1 haploinsufficiency reduces Notch-2 signaling during mouse lung development.
The forkhead box (Fox) f1 transcription factor is expressed in the mouse splanchnic (visceral) mesoderm, which contributes to development of the liver, gallbladder, lung, and intestinal tract. Pulmonary hemorrhage and peripheral microvascular defects were found in approximately half of the newborn Foxf1(+/-) mice, which expressed low levels of lung Foxf1 mRNA [low-Foxf1(+/-) mice]. Microvascular development was normal in the surviving newborn high-Foxf1(+/-) mice, which compensated for pulmonary Foxf1 haploinsufficiency and expressed wild-type Foxf1 levels. To identify expression of genes regulated by Foxf1, we used Affymetrix microarrays to determine embryonic lung RNAs influenced by Foxf1 haploinsufficiency. Embryonic Foxf1(+/-) lungs exhibited diminished expression of hepatocyte growth factor receptor c-Met, myosin VI, the transcription factors SP-3, BMI-1, ATF-2, and glucocorticoid receptor, and cell cycle inhibitors p53, p21(Cip1), retinoblastoma, and p107. Furthermore, Notch-2 signaling was decreased in embryonic Foxf1(+/-) lungs, as evidenced by significantly reduced levels of the Notch-2 receptor and the Notch-2 downstream target hairy enhancer of split-1. The severity of the Notch-2-signaling defect in 18-day postcoitus Foxf1(+/-) lungs correlated with Foxf1 mRNA levels. Disruption of pulmonary Notch-2 signaling continued in newborn low-Foxf1(+/-) mice, which died of lung hemorrhage and failed to compensate for Foxf1 haploinsufficiency. In contrast, in newborn high-Foxf1(+/-) lungs, Notch-2 signaling was restored to the level found in wild-type mice, which was associated with normal microvascular formation and survival. Foxf1 haploinsufficiency disrupted pulmonary expression of genes in the Notch-2-signaling pathway and resulted in abnormal development of lung microvasculature.
Kalinichenko
Vladimir V
VV
Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois, Chicago, IL 60607-7170, USA. vkalin@uic.edu
Gusarova
Galina A
GA
Kim
Il-Man
IM
Shin
Brian
B
Yoder
Helena M
HM
Clark
Jean
J
Sapozhnikov
Alexander M
AM
Whitsett
Jeffrey A
JA
Costa
Robert H
RH
D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D008168:Lung / Q000098:blood supply / Q000196:embryology* / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008833:Microcirculation; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012516:Osteosarcoma; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics; D050720:Retinoblastoma-Like Protein p107; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse; C497765:Notch2 protein, mouse; D009687:Nuclear Proteins; C489485:Rbl1 protein, mouse; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53