Embryonic Lethality and Defective Neural Tube Closure in Mice Lacking Squalene Synthase*

  title={Embryonic Lethality and Defective Neural Tube Closure in Mice Lacking Squalene Synthase*},
  author={Ryu-ichi Tozawa and Shu Ishibashi and Jun-ichi Osuga and Hiroaki Yagyu and Teruaki Oka and Zhong Chen and Ken Ohashi and St{\'e}phane Perrey and Futoshi Shionoiri and Naoya Yahagi and Kenji Harada and Takanari Gotoda and Yoshio Yazaki and Nobuhiro Yamada},
  journal={The Journal of Biological Chemistry},
  pages={30843 - 30848}
  • Ryu-ichi TozawaShu Ishibashi N. Yamada
  • Published 22 October 1999
  • Biology
  • The Journal of Biological Chemistry
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… 

Figures and Tables from this paper

Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver[S]

Liver-specific ablation of SS inhibits hepatic cholesterol biosynthesis and induces hypolipidemia without increasing significant mortality.

Early Embryonic Lethality Caused by Targeted Disruption of the 3-Hydroxy-3-methylglutaryl-CoA Reductase Gene*

It is speculated that the putative peroxisomal reductase gene, if existed, does not fully compensate for the lack of the ER enzyme at least in embryogenesis, and the haploid amount of Hmgcr gene is not rate-limiting in the hepatic cholesterol homeostasis.

Intestinal Deletion of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Promotes Expansion of the Resident Stem Cell Compartment

Loss of Hmgcr in the intestine is compatible with life through compensatory increases in intestinal absorptive surface area, LDLR expression, and expansion of the resident stem cell compartment.

Increased cholesterol biosynthesis and hypercholesterolemia in mice overexpressing squalene synthase in the liver Published, JLR Papers in Press, June 1, 2006.

It is demonstrated that transient upregulation of SS stimulates cholesterol biosynthesis as well as lipoprotein production, providing the first in vivo evidence that SS plays a regulatory role in cholesterol metabolism through modulation of HMG-CoA reductase activity and cholesterol biosynthetic activity.

Squalene synthase: structure and regulation.

Hydroxysteroid (17beta) dehydrogenase 7 activity is essential for fetal de novo cholesterol synthesis and for neuroectodermal survival and cardiovascular differentiation in early mouse embryos.

The data showed that the lack of HSD17B7 results in a blockage in the de novo cholesterol biosynthesis in mouse embryos in vivo, and H SD17BKO embryos die at embryonic day (E) 10.5.



Defective forebrain development in mice lacking gp330/megalin.

  • T. WillnowJ. Hilpert J. Herz
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1996
It is proposed that thegp330/megalin receptor is part of the maternal-fetal lipoprotein transport system and mediates the endocytic uptake of essential nutrients in the postgastrulation stage.

Knockout of the abetalipoproteinemia gene in mice: reduced lipoprotein secretion in heterozygotes and embryonic lethality in homozygotes.

  • M. RaabeL. Flynn S. Young
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1998
Half-normal MTP levels do not support normal levels of lipoprotein synthesis and secretion, and a complete deficiency of MTP causes lethal developmental abnormalities, perhaps because of an impaired capacity of the yolk sac to export lipids to the developing embryo.

Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function

Targeted gene disruption in the mouse shows that the Sonic hedgehog(Shh) gene plays a critical role in patterning of vertebrate embryonic tissues, including the brain and spinal cord, the axial

Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.

It is concluded that the LDL receptor is responsible in part for the low levels of VLDL, IDL, and LDL in wild-type mice and that adenovirus-encoded LDL receptors can acutely reverse the hypercholesterolemic effects of LDL receptor deficiency.

Knockout of the mouse apolipoprotein B gene results in embryonic lethality in homozygotes and protection against diet-induced hypercholesterolemia in heterozygotes.

It is indicated that apolipoprotein B plays an essential role in mouse embryonic development and when fed a diet rich in fat and cholesterol, heterozygous mice were protected from diet-induced hypercholesterolemia; these mice, which constitute an animal model for hypobetalipoproteinemia, should be useful for studying the effects of decreased apoliprotein B expression on atherogenesis.

A novel function for apolipoprotein B: lipoprotein synthesis in the yolk sac is critical for maternal-fetal lipid transport in mice.

It is demonstrated that apoB is normally expressed at early time points in embryonic development in yolk sac visceral endodermal cells, and that this expression is associated with the synthesis and secretion of apo B-containing lipoproteins.

RPR 107393, a potent squalene synthase inhibitor and orally effective cholesterol-lowering agent: comparison with inhibitors of HMG-CoA reductase.

RPR 107393 is an orally effective hypocholesterolemic agent in rats and marmosets that has greater efficacy than lovastatin or pravastatin in the marmoset and in vitro data demonstrate that these compounds are inhibitors of squalene synthase.