title: Interdependent TTF1 - ErbB4 interactions are critical for surfactant protein-B homeostasis in primary mouse lung alveolar type II cells.
abstract: ErbB4 receptor and thyroid transcription factor (TTF)-1 are important modulators of fetal alveolar type II (ATII) cell development and injury. ErbB4 is an upstream regulator of TTF-1, promoting its expression in MLE-12 cells, an ATII cell line. Both proteins are known to promote surfactant protein-B gene (SftpB) and protein (SP-B) expression, but their feedback interactions on each other are not known. We hypothesized that TTF-1 expression has a feedback effect on ErbB4 expression in an in-vitro model of isolated mouse ATII cells. We tested this hypothesis by analyzing the effects of overexpressing HER4 and Nkx2.1, the genes of ErbB4 and TTF-1 on TTF-1 and ErbB4 protein expression, respectively, as well as SP-B protein expression in primary fetal mouse lung ATII cells. Transient ErbB4 protein overexpression upregulated TTF-1 protein expression in primary fetal ATII cells, similarly to results previously shown in MLE-12 cells. Transient TTF-1 protein overexpression down regulated ErbB4 protein expression in both cell types. TTF-1 protein was upregulated in primary transgenic ErbB4-depleted adult ATII cells, however SP-B protein expression in these adult transgenic ATII cells was not affected by the absence of ErbB4. The observation that TTF-1 is upregulated in fetal ATII cells by ErbB4 overexpression and also in ErbB4-deleted adult ATII cells suggests additional factors interact with ErbB4 to regulate TTF-1 levels. We conclude that the interdependency of TTF-1 and ErbB4 is important for surfactant protein levels. The interactive regulation of ErbB4 and TTF-1 needs further elucidation.
authors.affiliation: Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA.|Hannover Medical School, Hannover, 30625, Germany.
authors.forename: Elger
authors.initials: E
authors.lastname: Marten
authors.affiliation: Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA.|Sackler School for Biomedical Sciences, Tufts University, Boston, MA, 02111, USA.
authors.forename: Heber C
authors.initials: HC
authors.lastname: Nielsen
authors.affiliation: Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA. cdammann@tuftsmedicalcenter.org.|Hannover Medical School, Hannover, 30625, Germany. cdammann@tuftsmedicalcenter.org.|Sackler School for Biomedical Sciences, Tufts University, Boston, MA, 02111, USA. cdammann@tuftsmedicalcenter.org.
authors.forename: Christiane E L
authors.initials: CE
authors.lastname: Dammann
keywords: Alveolar type II cells; ErbB4; Lung development; SP-B; TTF-1