Geranylgeranyl Diphosphate Synthase Modulates Fetal Lung Branching Morphogenesis Possibly through Controlling K-Ras Prenylation.
G proteins play essential roles in regulating fetal lung development, and any defects in their expression or function (eg, activation or posttranslational modification) can lead to lung developmental malformation. Geranylgeranyl diphosphate synthase (GGPPS) can modulate protein prenylation that is required for protein membrane-anchoring and activation. Here, we report that GGPPS regulates fetal lung branching morphogenesis possibly through controlling K-Ras prenylation during fetal lung development. GGPPS was continuously expressed in lung epithelium throughout whole fetal lung development. Specific deletion of geranylgeranyl diphosphate synthase 1 (Ggps1) in lung epithelium during fetal lung development resulted in neonatal respiratory distress syndrome-like disease. The knockout mice died at postnatal day 1 of respiratory failure, and the lungs showed compensatory pneumonectasis, pulmonary atelectasis, and hyaline membranes. Subsequently, we proved that lung malformations in Ggps1-deficient mice resulted from the failure of fetal lung branching morphogenesis. Further investigation revealed Ggps1 deletion blocked K-Ras geranylgeranylation and extracellular signal-related kinase 1 or 2/mitogen-activated protein kinase signaling, which in turn disturbed fibroblast growth factor 10 regulation on fetal lung branching morphogenesis. Collectively, our data suggest that GGPPS is essential for maintaining fetal lung branching morphogenesis, which is possibly through regulating K-Ras prenylation.
Ministry of Education Key Laboratory of Model Animal for Disease Study, the School of Medicine and Model Animal Research Center of Nanjing University, Nanjing, China; Department of Hepatopancreatobiliary Surgery, the Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China.
Wen-Jun
WJ
Jia
Ministry of Education Key Laboratory of Model Animal for Disease Study, the School of Medicine and Model Animal Research Center of Nanjing University, Nanjing, China.
Shan
S
Jiang
Ministry of Education Key Laboratory of Model Animal for Disease Study, the School of Medicine and Model Animal Research Center of Nanjing University, Nanjing, China.
Qiao-Li
QL
Tang
Ministry of Education Key Laboratory of Model Animal for Disease Study, the School of Medicine and Model Animal Research Center of Nanjing University, Nanjing, China.
Di
D
Shen
Ministry of Education Key Laboratory of Model Animal for Disease Study, the School of Medicine and Model Animal Research Center of Nanjing University, Nanjing, China.
Bin
B
Xue
State Key Laboratory of Medicinal Chemical Biology, the College of Life Sciences, Nankai University, Tianjin, China. Electronic address: ningwen108@nankai.edu.cn.
Wen
W
Ning
Ministry of Education Key Laboratory of Model Animal for Disease Study, the School of Medicine and Model Animal Research Center of Nanjing University, Nanjing, China. Electronic address: licj@nju.edu.cn.
Chao-Jun
CJ
Li
D000818:Animals; D015153:Blotting, Western; D051231:Farnesyltranstransferase / Q000378:metabolism*; D047109:Fetal Development; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism*; D017368:Protein Prenylation / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
C495428:Ggps1 protein, mouse; D009097:Multienzyme Complexes; D051231:Farnesyltranstransferase; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)