Teratogen-mediated inhibition of target tissue response to Shh signaling.

Veratrum alkaloids and distal inhibitors of cholesterol biosynthesis have been studied for more than 30 years as potent teratogens capable of inducing cyclopia and other birth defects. Here, it is shown that these compounds specifically block the Sonic hedgehog (Shh) signaling pathway. These teratogens did not prevent the sterol modification of Shh during autoprocessing but rather inhibited the response of target tissues to Shh, possibly acting through the sterol sensing domain within the Patched protein regulator of Shh response.

[1]  J. Rubenstein,et al.  Patterning of the embryonic forebrain , 1998, Current Opinion in Neurobiology.

[2]  M. Scott,et al.  Altered neural cell fates and medulloblastoma in mouse patched mutants. , 1997, Science.

[3]  K. G. Coleman,et al.  Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. , 1997, Science.

[4]  P. Beachy,et al.  Multiple roles of cholesterol in hedgehog protein biogenesis and signaling. , 1997, Cold Spring Harbor symposia on quantitative biology.

[5]  Johan Ericson,et al.  Two Critical Periods of Sonic Hedgehog Signaling Required for the Specification of Motor Neuron Identity , 1996, Cell.

[6]  C. Helms,et al.  Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly , 1996, Nature Genetics.

[7]  P. Beachy,et al.  Cholesterol Modification of Hedgehog Signaling Proteins in Animal Development , 1996, Science.

[8]  P. Beachy,et al.  Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function , 1996, Nature.

[9]  T. Mazzone,et al.  Cholesterol homeostasis is modulated by amphiphiles at transcriptional and post-transcriptional loci. , 1996, Journal of lipid research.

[10]  J. Metherall,et al.  Progesterone Inhibits Cholesterol Biosynthesis in Cultured Cells , 1996, The Journal of Biological Chemistry.

[11]  D. Strickland,et al.  Glycoprotein 330/Low Density Lipoprotein Receptor-related Protein-2 Mediates Endocytosis of Low Density Lipoproteins via Interaction with Apolipoprotein B100 (*) , 1995, The Journal of Biological Chemistry.

[12]  A. McMahon,et al.  Distribution of Sonic hedgehog peptides in the developing chick and mouse embryo. , 1995, Development.

[13]  T. Jessell,et al.  Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis , 1995, Cell.

[14]  Stephen C. Ekker,et al.  The product of hedgehog autoproteolytic cleavage active in local and long-range signalling , 1995, Nature.

[15]  J. J. Lee,et al.  Autoproteolysis in hedgehog protein biogenesis. , 1994, Science.

[16]  I. Guerrero,et al.  Subcellular localization of the segment polarity protein patched suggests an interaction with the wingless reception complex in Drosophila embryos. , 1994, Development.

[17]  G Salen,et al.  Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. , 1994, The New England journal of medicine.

[18]  T. Jessell,et al.  Control of cell pattern in the neural tube: Motor neuron induction by diffusible factors from notochord and floor plate , 1993, Cell.

[19]  T. Jessell,et al.  Early stages of motor neuron differentiation revealed by expression of homeobox gene Islet-1. , 1992, Science.

[20]  H. Yoshikawa.  Effects of drugs on cholesterol esterification in normal and Niemann-Pick type C fibroblasts: AY-9944, other cationic amphiphilic drugs and DMSO , 1991, Brain and Development.

[21]  K. Gibson,et al.  3-Hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured fibroblasts from patients with mevalonate kinase deficiency: differential response to lipid supplied by fetal bovine serum in tissue culture medium. , 1990, Journal of lipid research.

[22]  W. D. Nes,et al.  Inhibition of cholesterol synthesis and cell growth by 24(R,S),25-iminolanosterol and triparanol in cultured rat hepatoma cells. , 1989, The Journal of biological chemistry.

[23]  F. H. Schmidt,et al.  The effects of BM 15.766, an inhibitor of 7-dehydrocholesterol delta 7-reductase, on cholesterol biosynthesis in primary rat hepatocytes. , 1986, Biochemical pharmacology.

[24]  J. Watson,et al.  Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in hepatoma tissue culture cells by pure cholesterol and several cholesterol derivatives. Evidence supporting two distinct mechanisms.20l. , 1976, The Journal of biological chemistry.

[25]  R. Keeler,et al.  Teratogenic compounds of Veratrum californicum (Durand). V. Comparison of cyclopian effects of steroidal alkaloids from the plant and structurally related compounds from other sources. , 1968, Teratology.

[26]  C. Roux.  [TERATOGENIC ACTION OF TRIPARANOL IN ANIMALS]. , 1964, Archives francaises de pediatrie.