Forkhead Box m1 transcription factor is required for perinatal lung function.
The Forkhead Box m1 (Foxm1 or Foxm1b) transcription factor (previously called HFH-11B, Trident, Win, or MPP2) is an important positive regulator of DNA replication and mitosis in a variety of cell types. Global deletion of Foxm1 in Foxm1(-/-) mice is lethal in the embryonic period, causing multiple abnormalities in the liver, heart, lung, and blood vessels. In the present study, Foxm1 was deleted conditionally in the respiratory epithelium (epFoxm1(-/-)). Surprisingly, deletion of Foxm1 did not alter lung growth, branching morphogenesis, or epithelial proliferation but inhibited lung maturation and caused respiratory failure after birth. Maturation defects in epFoxm1(-/-) lungs were associated with decreased expression of T1-alpha and aquaporin 5, consistent with a delay of type I cell differentiation. Expression of surfactant-associated proteins A, B, C, and D was decreased by deletion of Foxm1. Foxm1 directly bound and induced transcriptional activity of the mouse surfactant protein B and A (Sftpb and Sftpa) promoters in vitro, indicating that Foxm1 is a direct transcriptional activator of these genes. Foxm1 is critical for surfactant homeostasis and lung maturation before birth and is required for adaptation to air breathing.
Kalin
Tanya V
TV
Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. kal4ti@cchmc.org
Wang
I-Ching
IC
Meliton
Lucille
L
Zhang
Yufang
Y
Wert
Susan E
SE
Ren
Xiaomeng
X
Snyder
Jonathan
J
Bell
Sheila M
SM
Graf
Lloyd
L
Whitsett
Jeffrey A
JA
Kalinichenko
Vladimir V
VV
D000818:Animals; D000831:Animals, Newborn; D002455:Cell Division / Q000502:physiology; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000166:cytology / Q000196:embryology* / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D036801:Parturition; D010455:Peptides / Q000235:genetics; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000502:physiology; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics; D037701:Pulmonary Surfactant-Associated Protein B / Q000235:genetics; D037721:Pulmonary Surfactant-Associated Protein C; D037663:Pulmonary Surfactant-Associated Protein D / Q000235:genetics; D012119:Respiration; D012131:Respiratory Insufficiency / Q000235:genetics / Q000503:physiopathology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000196:embryology / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D037662:Pulmonary Surfactant-Associated Protein A; D037701:Pulmonary Surfactant-Associated Protein B; D037721:Pulmonary Surfactant-Associated Protein C; D037663:Pulmonary Surfactant-Associated Protein D; C489680:Sftpc protein, mouse