Negative regulation of Hedgehog signaling by the cholesterogenic enzyme 7-dehydrocholesterol reductase
Abstract
Cholesterol regulates Hedgehog (Hh) signaling during early vertebrate development. Smith-Lemli-Opitz syndrome (SLOS) is caused by defects in 7-dehydrocholesterol reductase (DHCR7), an enzyme catalyzing the final step of cholesterol biosynthesis. Many developmental malformations attributed to SLOS occur in tissues and organs where Hh signaling is required for development, but the precise role of DHCR7 deficiency in this disease remains murky. We report that DHCR7 and Sonic Hedgehog (Shh) are co-expressed during midline development in Xenopus embryos. DHCR7 has previously been implicated to function as a positive regulator of Hh signaling that acts to regulate the cholesterol adduction of Hh ligand or to affect Hh signaling in the responding cell. We present gain- and loss-of-function analyses suggesting that DHCR7 functions as a negative regulator of Hh signaling at the level or downstream of Smoothened (Smo) and affects intracellular Hh signaling. Our analysis also raises the possibility that the human condition SLOS is caused not only by disruption of the enzymatic role of DHCR7 as a reductase in cholesterol biosynthesis, but may also involve defects in DHCR7 resulting in derepression of Shh signaling.
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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 [28]
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- Authors
- Koide, T., Hayata, T., & Cho, K. W. Y.
- Affiliations
- University of California, Irvine (US)
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2006-06-15
- Volume
- 133
- Issue
- 12
- Pages
- 2395-2405
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W2036144176
- Cited by
- 69
- References
- 60
- Citations by year
- 2025: 5 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 4 · 2020: 5 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 3 · 2013: 4 · 2012: 1
- FWCI
- 2.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-29507, R01HD029507)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- Hedgehog signaling, DHCR7, Smith-Lemli-Opitz syndrome, Sonic hedgehog, Smoothened, cholesterol biosynthesis, negative regulation of signaling, Xenopus embryo, developmental malformations
- MeSH terms
- Smoothened Receptor, Animals, Cholesterol, Embryonic Structures, Epistasis, Genetic, Humans, Receptors, Cell Surface, Xenopus laevis, Signal Transduction, Trans-Activators, Oligonucleotides, Antisense, In Situ Hybridization, Gene Expression Regulation, Developmental, Smith-Lemli-Opitz Syndrome, Body Patterning, Oligonucleotide Array Sequence Analysis, Xenopus Proteins, Receptors, G-Protein-Coupled, Oxidoreductases Acting on CH-CH Group Donors, Hedgehog Proteins
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