Foxa2 regulates alveolarization and goblet cell hyperplasia

The airways are lined by several distinct epithelial cells that play unique roles in pulmonary homeostasis; however, the mechanisms controlling their differentiation in health and disease are poorly understood. The winged helix transcription factor, FOXA2, is expressed in the foregut endoderm and in subsets of respiratory epithelial cells in the fetal and adult lung. Because targeted mutagenesis of the Foxa2 gene in mice is lethal before formation of the lung, its potential role in lung morphogenesis and homeostasis has not been determined. We selectively deleted Foxa2 in respiratory epithelial cells in the developing mouse lung. Airspace enlargement, goblet cell hyperplasia, increased mucin and neutrophilic infiltration were observed in lungs of the Foxa2-deleted mice. Experimental goblet cell hyperplasia caused by ovalbumin sensitization, interleukin 4 (IL4), IL13 and targeted deletion of the gene encoding surfactant protein C (SP-C), was associated with either absent or decreased expression of Foxa2 in airway epithelial cells. Analysis of lung tissue from patients with a variety of pulmonary diseases revealed a strong inverse correlation between FOXA2 and goblet cell hyperplasia. FOXA2 is required for alveolarization and regulates airway epithelial cell differentiation in the postnatal lung.

[1]  Jeffrey A. Whitsett,et al.  Conditional gene expression in the respiratory epithelium of the mouse , 2002, Transgenic Research.

[2]  Jeffrey A Whitsett,et al.  Inhibition of alveolarization and altered pulmonary mechanics in mice expressing GATA-6. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[3]  Y. Ho,et al.  Stimulation of Airway Mucin Gene Expression by Interleukin (IL)-17 through IL-6 Paracrine/Autocrine Loop* , 2003, The Journal of Biological Chemistry.

[4]  J. Whitsett,et al.  Pneumonitis and Emphysema in sp-C Gene Targeted Mice* , 2003, The Journal of Biological Chemistry.

[5]  J. Tichelaar,et al.  SP-B deficiency causes respiratory failure in adult mice. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[6]  M. Luster,et al.  Role of tumor necrosis factor in toluene diisocyanate asthma. , 2002, American journal of respiratory cell and molecular biology.

[7]  D. Sheppard,et al.  Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma , 2002, Nature Medicine.

[8]  Susan E. Wert,et al.  Early restriction of peripheral and proximal cell lineages during formation of the lung , 2002, Proceedings of the National Academy of Sciences of the United States of America.

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

[10]  M. Rothenberg,et al.  Interleukin-5-mediated Allergic Airway Inflammation Inhibits the Human Surfactant Protein C Promoter in Transgenic Mice* , 2001, The Journal of Biological Chemistry.

[11]  E. Gelfand,et al.  Temporal association between airway hyperresponsiveness and airway eosinophilia in ovalbumin-sensitized mice. , 2001, American journal of respiratory and critical care medicine.

[12]  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.

[13]  P. Sly,et al.  Endotoxin-induced lung maturation in preterm lambs is not mediated by cortisol. , 2000, American journal of respiratory and critical care medicine.

[14]  N. Daigle,et al.  Hepatocyte Nuclear Factor 3β (Foxa2) Is Dispensable for Maintaining the Differentiated State of the Adult Hepatocyte , 2000, Molecular and Cellular Biology.

[15]  M Ikegami,et al.  Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Tichelaar,et al.  Conditional Expression of Fibroblast Growth Factor-7 in the Developing and Mature Lung* , 2000, The Journal of Biological Chemistry.

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

[18]  J. Whitsett,et al.  Temporal-Spatial Distribution of Hepatocyte Nuclear Factor-3β in Developing Human Lung and Other Foregut Derivatives , 1998, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[19]  B. Sauer.  Inducible gene targeting in mice using the Cre/lox system. , 1998, Methods.

[20]  M. Gallup,et al.  Cloning of the Amino-terminal and 5′-Flanking Region of the HumanMUC5AC Mucin Gene and Transcriptional Up-regulation by Bacterial Exoproducts* , 1998, The Journal of Biological Chemistry.

[21]  M. Wills-Karp,et al.  Signal Transducer and Activator of Transcription Factor 6 (Stat6)-deficient Mice Are Protected from Antigen-induced Airway Hyperresponsiveness and Mucus Production , 1998, The Journal of experimental medicine.

[22]  J. Whitsett,et al.  Hepatocyte nuclear factor‐3β limits cellular diversity in the developing respiratory epithelium and alters lung morphogenesis in vivo , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[23]  J. Whitsett,et al.  Interleukin-4 alters epithelial cell differentiation and surfactant homeostasis in the postnatal mouse lung. , 1997, American journal of respiratory cell and molecular biology.

[24]  L. Lim,et al.  Thyroid transcription factor-1, hepatocyte nuclear factor-3beta, surfactant protein B, C, and Clara cell secretory protein in developing mouse lung. , 1996, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[25]  B. Stripp,et al.  Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Whitsett,et al.  Hepatocyte nuclear factor 3 activates transcription of thyroid transcription factor 1 in respiratory epithelial cells , 1996, Molecular and cellular biology.

[27]  W. Cardoso,et al.  Transcription factors and pattern formation in the developing lung. , 1995, The American journal of physiology.

[28]  T.F. Schuessler,et al.  A computer-controlled research ventilator for small animals: design and evaluation , 1995, IEEE Transactions on Biomedical Engineering.

[29]  B. Stripp,et al.  Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Gitlin,et al.  Role of hepatocyte nuclear factor-3 alpha and hepatocyte nuclear factor-3 beta in Clara cell secretory protein gene expression in the bronchiolar epithelium. , 1995, The Biochemical journal.

[31]  R. Lauro,et al.  The lung-specific surfactant protein B gene promoter is a target for thyroid transcription factor 1 and hepatocyte nuclear factor 3, indicating common factors for organ-specific gene expression along the foregut axis , 1994, Molecular and cellular biology.

[32]  J. Rossant,et al.  HNF-3β is essential for node and notochord formation in mouse development , 1994, Cell.

[33]  Thomas M. Jessell,et al.  The winged-helix transcription factor HNF-3β is required for notochord development in the mouse embryo , 1994, Cell.

[34]  J. Rossant,et al.  HNF-3 beta is essential for node and notochord formation in mouse development. , 1994, Cell.

[35]  J. Rossant,et al.  The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins. , 1993, Development.

[36]  K. Kaestner,et al.  Postimplantation expression patterns indicate a role for the mouse forkhead/HNF-3 alpha, beta and gamma genes in determination of the definitive endoderm, chordamesoderm and neuroectoderm. , 1993, Development.

[37]  J. Gitlin,et al.  Identification of hepatocyte nuclear factor-3 binding sites in the Clara cell secretory protein gene. , 1993, The Biochemical journal.

[38]  B. Hogan,et al.  Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo. , 1993, Development.

[39]  J. Whitsett,et al.  Transcriptional elements from the human SP-C gene direct expression in the primordial respiratory epithelium of transgenic mice. , 1993, Developmental biology.

[40]  B. Stripp,et al.  cis-acting elements that confer lung epithelial cell expression of the CC10 gene. , 1992, The Journal of biological chemistry.

[41]  M. Terzaghi-Howe,et al.  Basal cells are the progenitors of primary tracheal epithelial cell cultures. , 1992, Experimental cell research.

[42]  A. Scott,et al.  Interleukin-1 induces mucus secretion from mouse intestinal explants. , 1987, International archives of allergy and applied immunology.

[43]  C. Plopper,et al.  Differentiation of tracheal epithelium during fetal lung maturation in the rhesus monkey Macaca mulatta. , 1986, The American journal of anatomy.