title: Embryonic lethality and defective neural tube closure in mice lacking squalene synthase.
abstract: Squalene synthase (SS) catalyzes the reductive head-to-head condensation of two molecules of farnesyl diphosphate to form squalene, the first specific intermediate in the cholesterol biosynthetic pathway. We used gene targeting to knock out the mouse SS gene. The mice heterozygous for the mutation (SS+/-) were apparently normal. SS+/- mice showed 60% reduction in the hepatic mRNA levels of SS compared with SS+/+ mice. Consistently, the SS enzymatic activities were reduced by 50% in the liver and testis. Nevertheless, the hepatic cholesterol synthesis was not different between SS+/- and SS+/+ mice, and plasma lipoprotein profiles were not different irrespective of the presence of the low density lipoprotein receptor, indicating that SS is not a rate-limiting enzyme in the cholesterol biosynthetic pathway. The mice homozygous for the disrupted SS gene (SS-/-) were embryonic lethal around midgestation. E9.5-10.5 SS-/- embryos exhibited severe growth retardation and defective neural tube closure. The lethal phenotype was not rescued by supplementing the dams either with dietary squalene or cholesterol. We speculate that cholesterol is required for the development, particularly of the nervous system, and that the chorioallantoic circulatory system is not mature enough to supply the rapidly growing embryos with maternal cholesterol at this developmental stage.
authors.affiliation: Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Tozawa
authors.forename: S
authors.initials: S
authors.lastname: Ishibashi
authors.forename: J
authors.initials: J
authors.lastname: Osuga
authors.forename: H
authors.initials: H
authors.lastname: Yagyu
authors.forename: T
authors.initials: T
authors.lastname: Oka
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: K
authors.initials: K
authors.lastname: Ohashi
authors.forename: S
authors.initials: S
authors.lastname: Perrey
authors.forename: F
authors.initials: F
authors.lastname: Shionoiri
authors.forename: N
authors.initials: N
authors.lastname: Yahagi
authors.forename: K
authors.initials: K
authors.lastname: Harada
authors.forename: T
authors.initials: T
authors.lastname: Gotoda
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
authors.forename: N
authors.initials: N
authors.lastname: Yamada
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D003433:Crosses, Genetic; D005314:Embryonic and Fetal Development; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D005313:Fetal Death; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D005865:Gestational Age; D006579:Heterozygote; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009436:Neural Tube Defects / Q000201:enzymology / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013737:Testis / Q000201:enzymology
chemical_list: D008074:Lipoproteins; D012333:RNA, Messenger; D011973:Receptors, LDL; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase