title: Deficiency in pulmonary surfactant proteins in mice with fatty acid binding protein 4-Cre-mediated knockout of the tuberous sclerosis complex 1 gene.
abstract: Tuberous sclerosis complex 1 (TSC1) forms a heterodimmer with tuberous sclerosis complex 2, to inhibit signalling by the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). The mTORC1 stimulates cell growth by promoting anabolic cellular processes, such as gene transcription and protein translation, in response to growth factors and nutrient signals. Originally designed to test the role of TSC1 in adipocyte function, mice in which the gene for TSC1 was specifically deleted by the fatty acid binding protein 4 (FABP4)-Cre (Fabp4-Tsc1cKO mice) died prematurely within 48 h after birth. The Fabp4-Tsc1cKO mouse revealed a much smaller phenotype relative to the wild-type littermates. Maternal administration of rapamycin, a classical mTOR inhibitor, significantly increased the survival time of Fabp4-Tsc1cKO mice for up to 23 days. Both macroscopic and microscopic haemorrhages were observed in the lungs of Fabp4-Tsc1cKO mice, while other tissues showed no significant changes. Levels of surfactant proteins A and B demonstrated a significant decrease in the Fabp4-Tsc1cKO mice, which was rescued by maternal injection of rapamycin. Co-localization of FABP4 or TSC1 with surfactant protein B was also detected in neonatal pulmonary tissues. Our study suggests that TSC1-mTORC1 may be critical for the synthesis of surfactant proteins A and B.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, People's Republic of China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Xiang
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Ziru
authors.initials: Z
authors.lastname: Li
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
authors.forename: Chaoshu
authors.initials: C
authors.lastname: Tang
authors.forename: Guang
authors.initials: G
authors.lastname: Sun
authors.forename: Yin
authors.initials: Y
authors.lastname: Li
authors.forename: Weizhen
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D008168:Lung / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D037662:Pulmonary Surfactant-Associated Protein A / Q000096:biosynthesis* / Q000172:deficiency; D037701:Pulmonary Surfactant-Associated Protein B / Q000096:biosynthesis* / Q000172:deficiency; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D037662:Pulmonary Surfactant-Associated Protein A; D037701:Pulmonary Surfactant-Associated Protein B; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus