title: ErbB4 is an upstream regulator of TTF-1 fetal mouse lung type II cell development in vitro.
abstract: TTF-1 is an important transcription factor in lung development and lung disease and is essential for lung cell differentiation, specifically surfactant protein (Sftp) expression. The molecular mechanisms that drive the expression and transcriptional control of TTF-1 are not fully understood. In the fetal lung, ErbB4 functions as a transcriptional co-factor and regulates the timely onset of fetal Sftp expression. We speculate that ErbB4 is an upstream regulator of TTF-1 and regulates Sftpb expression via this pathway in alveolar type II cells. Neuregulin-induced ErbB4 and TTF-1 signaling interactions were studied by co-immunoprecipitation and confocal microscopy. Overexpression of ErbB4 and TTF-1 was analyzed in its effect on cell viability, Sftpb expression, TTF-1 expression, and Sftpb and TTF-1 promoter activity. The effect of ErbB4 deletion and ErbB4 nuclear translocation on TTF-1 expression was studied in primary fetal type II epithelial cells, isolated from transgenic HER4(heart(-/-)) mice. ErbB4 ligand neuregulin induces ErbB4 and TTF-1 co-precipitation and nuclear colocalization. Combined ErbB4 and TTF-1 overexpression inhibits cell viability, while promoting Sftpb expression more than single overexpression of each protein. NRG stimulates TTF-1 expression in ErbB4-overexpressing epithelial cells, while this effect is absent in ErbB4-depleted cells. In primary fetal type II cells, ErbB4 nuclear translocation is critical for its regulation of TTF-1-induced Sftpb upregulation. TTF-1 overexpression did not overcome this important requirement. We conclude that ErbB4 is a critical upstream regulator of TTF-1 in type II epithelial cells and that this interaction is important for Sftpb regulation.
authors.affiliation: Department of Pediatrics, Hannover Medical School, Hannover 30625, Germany; Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Katja
authors.initials: K
authors.lastname: Zscheppang
authors.affiliation: Department of Pediatrics, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Giese
authors.affiliation: Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hoenzke
authors.affiliation: Department of Pediatrics, Hannover Medical School, Hannover 30625, Germany; Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Wiegel
authors.affiliation: Department of Pediatrics, Hannover Medical School, Hannover 30625, Germany; Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, Boston, MA 02111, USA; Sackler School for Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA. Electronic address: cdammann@tuftsmedicalcenter.org.
authors.forename: Christiane E L
authors.initials: CEL
authors.lastname: Dammann
mesh_terms: D056809:Alveolar Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D005333:Fetus / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008954:Models, Biological; D020880:Neuregulins / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D037701:Pulmonary Surfactant-Associated Protein B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; D020880:Neuregulins; D037701:Pulmonary Surfactant-Associated Protein B; D012333:RNA, Messenger; D014157:Transcription Factors; C504004:Ttf1 protein, mouse; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4
keywords: Lung development; Neuregulin; Surfactant; Type II cell