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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.

SUBMITTER: Zscheppang K

PROVIDER: S-EPMC3835615 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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ErbB4 is an upstream regulator of TTF-1 fetal mouse lung type II cell development in vitro.

Zscheppang Katja K Giese Ulrike U Hoenzke Stefan S Wiegel Dorothea D Dammann Christiane E L CEL

Biochimica et biophysica acta 20130708 12

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 expres ...[more]

PMID: 23845988

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Project description:BACKGROUND: In human, respiratory distress of the neonates, which occurs in prematurity, is prevalent in male. Late in gestation, maturation of type II pneumonocytes, and consequently the surge of surfactant synthesis are delayed in male fetuses compared with female fetuses. Although the presence of higher levels of androgens in male fetuses is thought to explain this sex difference, the identity of genes involved in lung maturation that are differentially modulated according to fetal sex is unknown. We have studied the sex difference in developing mouse lung by gene profiling during a three-day gestational window preceding and including the emergence of mature PTII cells (the surge of surfactant synthesis in the mouse occurs on GD 17.5). METHODS: Total RNA was extracted from lungs of male and female fetal mice (gestation days 15.5, 16.5, and 17.5), converted to cRNA, labeled with biotin, and hybridized to oligonucleotide microarrays (Affymetrix MOE430A). Analysis of data was performed using MAS5.0, LFCM and Genesis softwares. RESULTS: Many genes involved in lung maturation were expressed with no sex difference. Of the approximative 14,000 transcripts covered by the arrays, only 83 genes presented a sex difference at one or more time points between GDs 15.5 and 17.5. They include genes involved in hormone metabolism and regulation (i.e. steroidogenesis pathways), apoptosis, signal transduction, transcriptional regulation, and lipid metabolism with four apolipoprotein genes. Genes involved in immune functions and other metabolisms also displayed a sex difference. CONCLUSION: Among these sexually dimorphic genes, some may be candidates for a role in lung maturation. Indeed, on GD 17.5, the sex difference in surfactant lipids correlates with the sex difference in pulmonary expression of apolipoprotein genes, which are involved in lipid transport. This suggests a role for these genes in the surge of surfactant synthesis. Our results would help to identify novel genes involved in the physiopathology of the respiratory distress of the neonates.

Dataset Information

ErbB4 is an upstream regulator of TTF-1 fetal mouse lung type II cell development in vitro.

Publications

ErbB4 is an upstream regulator of TTF-1 fetal mouse lung type II cell development in vitro.

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