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.
Cooper
M K
MK
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Porter
J A
JA
Young
K E
KE
Beachy
P A
PA
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D002642:Chick Embryo; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism*; D046508:Culture Techniques; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D053823:Hedgehog Proteins; D051542:Hepatocyte Nuclear Factor 3-beta; D016142:Holoprosencephaly / Q000139:chemically induced; D018398:Homeodomain Proteins / Q000096:biosynthesis; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000096:biosynthesis; D051763:PAX7 Transcription Factor; D000072079:Patched Receptors; D011506:Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000187:drug effects; D013723:Teratogens / Q000494:pharmacology*; D014053:Tomatine / Q000031:analogs & derivatives / Q000494:pharmacology; D015534:Trans-Activators; D014157:Transcription Factors; D014308:Triparanol / Q000494:pharmacology; D014704:Veratrum Alkaloids / Q000494:pharmacology*; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / Q000494:pharmacology
D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051763:PAX7 Transcription Factor; D000072079:Patched Receptors; D011506:Proteins; D011956:Receptors, Cell Surface; D013723:Teratogens; D015534:Trans-Activators; D014157:Transcription Factors; D014704:Veratrum Alkaloids; C063843:insulin gene enhancer binding protein Isl-1; D051542:Hepatocyte Nuclear Factor 3-beta; C010206:jervine; C003677:tomatidine; D014053:Tomatine; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; D014308:Triparanol; D002784:Cholesterol; C000541:cyclopamine