GSE97789
TGF-beta signaling pathway and male disadvantage in the pathogenesis of the bronchial pulmonary dysplasia
Insufficient activation of the TGF-b signaling pathway leads to abnormalities in embryonic lung development. Herein, we determined the effect of the epithelial over-activation of the TGF-b signaling pathway in the embryonic lung development by expressing the constitutive active form of the Tgf-b receptor 1. Ectopic activation of the TGF-b signaling pathway in the lung embryonic epithelium resulted in a complex and lethal phenotype in male mice, but not in female mice. Mutant male embryos died at birth due to their inability to breathe, and showed a bronchial-pulmonary-dysplasia-like phenotype which included reduced lung size, increased alveolar wall thickness, increased cellular density of the lung parenchyma and diminished population of club cells. While the NOTCH signaling, pathway was not affected, we found that protein expression of the endodermal stem cell marker Ssea1 was strongly reduced in proximal lung airways of male lungs. In the distal lung epithelium, ectopic activation of the TGF-b signaling pathway resulted in the increased number of Sox9+ alveolar progenitor cells. Moreover, deletion of one Sox9 allele reduced the severity of the phenotype in mutant males, suggesting that TGF-b mediated over-expression of Sox9 protein is critical for the development of the bronchial pulmonary dysplasia-like phenotype displayed by the mutant male animals. Gene expression profiling identified 993 differentially expressed genes in the mutant male lungs compared to the control male lung. Several of these genes, such as Cbr2 and Hp, are expressed by the club cell and were downregulated by the TGF-b signaling pathway in the mutant male lung. Others such as Spock2, Adamtsl2 and Adamts18 were previous found to be linked to fetal lung disease and indispensable for proper lung development. Finally, we showed that injection of b-estradiol in the pregnant female rescued the phenotype in the mutant male embryos which suggests a critical role of the sex hormones in the pathogenesis of the bronchial pulmonary dysplasia disease. In conclusion, we have established a novel sex-specific mouse model that may be helpful in elucidating specific pathways by which sex adversely affects the well-known but obscure more adverse outcome of male patients. Overall design: A total of 8 samples were analyzed: 2 control E17.5 lung female, 2 mutant E17.5 lung female, 2 control E17.5 lung male, 2 mutant E17.5 lung male.