Wild-type levels of the mouse Forkhead Box f1 gene are essential for lung repair.

The Forkhead Box (Fox) family of transcription factors plays important roles in regulating expression of genes involved in cellular proliferation and differentiation. In a previous study, we showed that newborn foxf1(+/-) mice with diminished Foxf1 levels exhibited abnormal formation of pulmonary alveoli and capillaries and died postnatally. Interestingly, surviving newborn foxf1(+/-) mice exhibited increased pulmonary Foxf1 levels and normal adult lung morphology, suggesting that wild-type Foxf1 levels are required for lung development and function. The present study was conducted to determine whether adult foxf1(+/-) mice were able to undergo lung repair similar to that observed in wild-type mice. We demonstrated that adult foxf1(+/-) mice died from severe lung hemorrhage after butylated hydroxytoluene (BHT) lung injury and that this phenotype was associated with a 10-fold decrease in pulmonary Foxf1 expression and increased alveolar endothelial cell apoptosis that disrupted capillary integrity. Furthermore, BHT-induced lung hemorrhage of adult foxf1(+/-) mice was associated with a drastic reduction in expression of the Flk-1, bone morphogenetic protein-4, surfactant protein B, platelet endothelial cell adhesion molecule, and vascular endothelial cadherin genes, whereas the expression of these genes was either transiently diminished or increased in wild-type lungs after BHT injury. Because these proteins are critical for lung morphogenesis and endothelial homeostasis, their decreased mRNA levels are likely contributing to BHT-induced lung hemorrhage in foxf1(+/-) mice. Collectively, our data suggest that sustained expression of Foxf1 is essential for normal lung repair and endothelial cell survival in response to pulmonary cell injury.

[1]  Ondine Cleaver,et al.  Induction of Pancreatic Differentiation by Signals from Blood Vessels , 2001, Science.

[2]  J. Rossant,et al.  Liver Organogenesis Promoted by Endothelial Cells Prior to Vascular Function , 2001, Science.

[3]  R. Costa,et al.  Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Simon C Watkins,et al.  Defects in pulmonary vasculature and perinatal lung hemorrhage in mice heterozygous null for the Forkhead Box f1 transcription factor. , 2001, Developmental biology.

[5]  P. Carlsson,et al.  Haploinsufficiency of the forkhead gene Foxf1, a target for sonic hedgehog signaling, causes lung and foregut malformations. , 2001, Development.

[6]  R. Costa,et al.  Earlier expression of the transcription factor HFH‐11B diminishes induction of p21CIP1/WAF1 levels and accelerates mouse hepatocyte entry into S‐phase following carbon tetrachloride liver injury , 2001, Hepatology.

[7]  L. Lim,et al.  Transcription factors in mouse lung development and function. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[8]  L. Lim,et al.  Differential expression of forkhead box transcription factors following butylated hydroxytoluene lung injury. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[9]  E. R. Taylor,et al.  SIGNALING THROUGH CD31 PROTECTS ENDOTHELIAL CELLS FROM APOPTOSIS , 2001, Transplantation.

[10]  A. Mohsenin,et al.  PECAM‐1 shedding during apoptosis generates a membrane‐anchored truncated molecule with unique signaling characteristics , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  P. Carlsson,et al.  The forkhead transcription factor Foxf1 is required for differentiation of extra-embryonic and lateral plate mesoderm. , 2001, Development.

[12]  A. Malik,et al.  Reversibility of increased microvessel permeability in response to VE-cadherin disassembly. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[13]  C. D’Angio,et al.  Bcl-2 Family Gene Expression during Severe Hyperoxia Induced Lung Injury , 2000, Laboratory Investigation.

[14]  Simon C Watkins,et al.  Elevated Levels of Hepatocyte Nuclear Factor 3β in Mouse Hepatocytes Influence Expression of Genes Involved in Bile Acid and Glucose Homeostasis , 2000, Molecular and Cellular Biology.

[15]  S. Duncan.  Transcriptional regulation of liver development , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[16]  K. Kaestner,et al.  The Hepatocyte Nuclear Factor 3 (HNF3 or FOXA) Family in Metabolism , 2000, Trends in Endocrinology & Metabolism.

[17]  R. Watkins,et al.  Expression of Vascular Endothelial Growth Factor and Flk-1 in Developing and Glucocorticoid-Treated Mouse Lung , 2000, Pediatric Research.

[18]  P. Carlsson,et al.  Forkhead transcription factor FoxF2 is expressed in mesodermal tissues involved in epithelio‐mesenchymal interactions , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[19]  R. Homer,et al.  Interleukin-6-induced protection in hyperoxic acute lung injury. , 2000, American journal of respiratory cell and molecular biology.

[20]  K. Kaestner,et al.  Unified nomenclature for the winged helix/forkhead transcription factors. , 2000, Genes & development.

[21]  R. Costa,et al.  Premature Expression of the Winged Helix Transcription Factor HFH-11B in Regenerating Mouse Liver Accelerates Hepatocyte Entry into S Phase , 1999, Molecular and Cellular Biology.

[22]  G. Randolph,et al.  Migration of leukocytes across endothelium and beyond: molecules involved in the transmigration and fate of monocytes , 1999, Journal of leukocyte biology.

[23]  B. Hogan,et al.  Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development. , 1999, Development.

[24]  J. Lingrel,et al.  Lung Kruppel-like Factor, a Zinc Finger Transcription Factor, Is Essential for Normal Lung Development* , 1999, The Journal of Biological Chemistry.

[25]  J. Whitsett,et al.  Molecular mechanisms controlling lung morphogenesis , 1999, Clinical genetics.

[26]  L. Yang,et al.  Retrovirus-mediated HO gene transfer into endothelial cells protects against oxidant-induced injury. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[27]  G. Breier,et al.  Identification of vascular endothelial growth factor (VEGF) receptor-2 (Flk-1) promoter/enhancer sequences sufficient for angioblast and endothelial cell-specific transcription in transgenic mice. , 1999, Blood.

[28]  S. Gory-Fauré,et al.  Role of vascular endothelial-cadherin in vascular morphogenesis. , 1999, Development.

[29]  K. Zaret,et al.  Developmental competence of the gut endoderm: genetic potentiation by GATA and HNF3/fork head proteins. , 1999, Developmental biology.

[30]  A. Choi,et al.  Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. , 1999, The Journal of clinical investigation.

[31]  P. Carlsson,et al.  FREAC-1 contains a cell-type-specific transcriptional activation domain and is expressed in epithelial-mesenchymal interfaces. , 1998, Developmental biology.

[32]  P. Carlsson,et al.  The Human Forkhead Protein FREAC-2 Contains Two Functionally Redundant Activation Domains and Interacts with TBP and TFIIB* , 1998, The Journal of Biological Chemistry.

[33]  H. Westphal,et al.  Sonic hedgehog is essential to foregut development , 1998, Nature Genetics.

[34]  L. Lau,et al.  The -4 kilobase promoter region of the winged helix transcription factor HNF-3alpha gene elicits transgene expression in mouse embryonic hepatic and intestinal diverticula. , 1998, The International journal of developmental biology.

[35]  T. Sugiyama,et al.  Mouse forkhead (winged helix) gene LUN encodes a transactivator that acts in the lung. , 1998, Genomics.

[36]  L. Lim,et al.  The winged helix transcriptional activator HFH-8 is expressed in the mesoderm of the primitive streak stage of mouse embryos and its cellular derivatives , 1997, Mechanisms of Development.

[37]  Á. Corbí,et al.  Cloning of the human platelet endothelial cell adhesion molecule-1 promoter and its tissue-specific expression. Structural and functional characterization. , 1996, Journal of immunology.

[38]  N. Copeland,et al.  bcl-w, a novel member of the bcl-2 family, promotes cell survival. , 1996, Oncogene.

[39]  W. Knöchel,et al.  Five years on the wings of fork head , 1996, Mechanisms of Development.

[40]  B. Hogan,et al.  Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis. , 1996, Development.

[41]  P. Carlsson,et al.  Differential Activation of Lung-specific Genes by Two Forkhead Proteins, FREAC-1 and FREAC-2 (*) , 1996, The Journal of Biological Chemistry.

[42]  S. Burley,et al.  Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5 , 1993, Nature.

[43]  J. Darnell,et al.  Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head. , 1991, Genes & development.

[44]  J E Darnell,et al.  Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes , 1989, Molecular and cellular biology.

[45]  Andrew A. Marino,et al.  Lung Damage in Mice Following Intraperitoneal Injection of Butylated Hydroxytoluene 1 , 1972, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[46]  R. Costa,et al.  Atypical mouse cerebellar development is caused by ectopic expression of the forkhead box transcription factor HNF-3beta. , 2001, Gene expression.

[47]  J. Whitsett,et al.  Surfactant protein-B-deficient mice are susceptible to hyperoxic lung injury. , 1999, American journal of respiratory cell and molecular biology.

[48]  E. Dejana,et al.  The vascular endothelial-cadherin promoter directs endothelial-specific expression in transgenic mice. , 1999, Blood.

[49]  I. Adamson,et al.  Lung injury induced by butylated hydroxytoluene: cytodynamic and biochemical studies in mice. , 1977, Laboratory investigation; a journal of technical methods and pathology.