Cited2 is required for fetal lung maturation.
Lung maturation at the terminal sac stage of lung development is characterized by a coordinated increase in terminal sac formation and vascular development in conjunction with the differentiation of alveolar type I and type II epithelial cells. The Cited2-Tcfap2a/c complex has been shown to activate transcription of Erbb3 and Pitx2c during mouse development. In this study, we show that E17.5 to E18.5 Cited2-null lungs had significantly reduced terminal sac space due to an altered differentiation of type I and type II alveolar epithelial cells. In addition, E17 Cited2-null lungs exhibited a decrease in the number of apoptotic cells, contributing to the loss in airspace. Consistent with the phenotype, genes associated with alveolar cell differentiation and survival were differentially expressed in Cited2-null fetal lungs compared to those of wild-type littermates. Moreover, expression of Cebpa, a key regulator of airway epithelial maturation, was significantly decreased in Cited2-null fetal lungs. Cited2 and Tcfap2c were present on the Cebpa promoter in E18.5 lungs to activate Cebpa transcription. We propose that the Cited2-Tcfap2c complex controls lung maturation by regulating Cebpa expression. Understanding the function of this complex may provide novel therapeutic strategies for patients with respiratory distress syndromes.
Xu
Bing
B
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Qu
Xiaoling
X
Gu
Shi
S
Doughman
Yong-Qiu
YQ
Watanabe
Michiko
M
Dunwoodie
Sally L
SL
Yang
Yu-Chung
YC
D000818:Animals; D017209:Apoptosis; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D008168:Lung / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D050656:Transcription Factor AP-2 / Q000378:metabolism
D022763:CCAAT-Enhancer-Binding Protein-alpha; C110087:Cited2 protein, mouse; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; C583890:Tfap2c protein, mouse; D015534:Trans-Activators; D050656:Transcription Factor AP-2