Teratogen-Mediated Inhibition of Target Tissue Response to Shh Signaling
Abstract
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.
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Low cholesterol levels may impair sonic hedgehog signaling and cause the striking developmental malformations in SLOS.
“Low cholesterol levels may impair sonic hedgehog signaling and cause the striking developmental malformations. Activity of this signaling factor and its distribution are regulated by posttranslational attachment of cholesterol to its amino terminus [26,27,28].”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [27]
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- Authors
- Cooper, M. K., Porter, J. A., Young, K. E., & Beachy, P. A.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Porter, Jeffery A.
- Beachy, Philip A.
- ORCID
- Beachy, Philip A.
- Venue
- Science
- Published
- 1998-06-05
- Volume
- 280
- Issue
- 5369
- Pages
- 1603-1607
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2002249795
- Cited by
- 848
- References
- 26
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 12 · 2023: 13 · 2022: 18 · 2021: 9 · 2020: 16 · 2019: 25 · 2018: 22 · 2017: 25 · 2016: 26 · 2015: 27 · 2014: 34 · 2013: 31 · 2012: 50
- FWCI
- 14.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- teratogens, Sonic hedgehog signaling, veratrum alkaloids, cholesterol biosynthesis inhibitors, cyclopia, congenital malformations, sterol-sensing domain
- MeSH terms
- Abnormalities, Drug-Induced, Patched Receptors, Animals, trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride, Cell Membrane, Central Nervous System, Chick Embryo, Cholesterol, DNA-Binding Proteins, Endoplasmic Reticulum, Membrane Proteins, Muscle Proteins, Nerve Tissue Proteins, Nuclear Proteins, Proteins, Receptors, Cell Surface, Teratogens, Tomatine, Transcription Factors, Triparanol, Veratrum Alkaloids, Signal Transduction, Trans-Activators, Holoprosencephaly, Homeodomain Proteins, Culture Techniques, Hepatocyte Nuclear Factor 3-beta, PAX7 Transcription Factor, Hedgehog Proteins, LIM-Homeodomain Proteins
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