Molecular mechanisms underlying limb anomalies associated with cholesterol deficiency during gestation: implications of Hedgehog signaling

Gofflot, F.

doi:10.1093/hmg/ddg129

Cited by 80Congenital limb and hand anomaliesHedgehog Signaling Pathway StudiesDevelopmental Biology and Gene Regulation

Molecular mechanisms underlying limb anomalies associated with cholesterol deficiency during gestation: implications of Hedgehog signaling

Gofflot, F.·2003·Human Molecular Genetics

DOI 10.1093/hmg/ddg129

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Abstract

Human disorders caused by inborn errors of cholesterol biosynthesis are characterized by dysmorphogenesis of multiple organs. This includes limb malformations that are observed at high frequency in some disorders, such as the Smith-Lemli-Opitz syndrome, indicating a pivotal role of cholesterol in limb morphogenesis. Recently, it has been demonstrated that cholesterol can modulate the activity of the Hedgehog proteins, that act as morphogens to regulate the precise patterning of many embryonic structures, among which the developing limbs. To provide insight in the functions of cholesterol during limb development and in the potential role of Hedgehog signaling in the genesis of limb defects, we developed an in vivo rat model of cholesterol deficiency. We show here that treatment with Triparanol, a distal inhibitor of cholesterol biosynthesis, induced patterning defects of the autopod at high frequency, including pre-axial syndactyly and post-axial polydactyly, thus reproducing limb anomalies frequently observed in humans. Using in situ hybridization, we show that these malformations originate from a modification of Sonic Hedgehog signaling in the limb bud at 13 days post-coitum, leading to a deficiency of the anterior part of the limb. This deficiency results in an imbalance of Indian Hedgehog expression in the forming cartilage, ultimately leading to reduced interdigital apoptosis and syndactyly. Our study thus unravels the molecular mechanisms underlying the genesis of limb defects associated with cholesterol deficiency in rodents, and most probably in humans.

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Cholesterol derivatization of hedgehog proteins is required for its signaling in bone formation.
“Finally, cholesterol derivatization of hedgehog proteins is required for its signaling in bone formation (340,341).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [341]
The Introduction describes cholesterol attachment to Hedgehog proteins, and “Unique role of cholesterol for proper activity of Shh in the limb” says cholesterol is required for long-range Shh activity during limb patterning. It explicitly says cholesterol is not required for short-range signaling there. The paper therefore does not establish that cholesterol derivatization is required for Hedgehog signaling generally in bone formation; no page numbers are provided in our copy. (LLM, conf=0.88)
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Authors: Gofflot, F.
Affiliations: UCLouvain (BE)
Corresponding author: Gofflot, F.
ORCID: Gofflot, F.
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2003-05-15
Volume: 12
Issue: 10
Pages: 1187-1198
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/ddg129
OpenAlex: W2133019309
Semantic Scholar: 1f896a7106ae3d8855805701bb21e1d73026580c
Cited by: 80
References: 53
Citations by year: 2025: 1 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 6 · 2015: 5 · 2014: 6 · 2013: 5 · 2012: 6
FWCI: 4.23
Type: journal article
Language: en
Open access: closed
Locations: Human Molecular Genetics (publishedVersion)
PubMed (publishedVersion)
DIAL (Catholic University of Leuven) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords: cholesterol deficiency, limb malformations, Hedgehog signaling, Sonic hedgehog, Indian hedgehog, postaxial polydactyly, triparanol, cholesterol synthesis inhibition, limb bud, Smith-Lemli-Opitz syndrome, rat model
MeSH terms: Animals, Hypolipidemic Agents, Bone and Bones, Cholesterol, Dose-Response Relationship, Drug, Teratogens, Triparanol, Signal Transduction, Trans-Activators, Rats, Wistar, Limb Deformities, Congenital, Limb Buds, Rats, Hedgehog Proteins

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Molecular mechanisms underlying limb anomalies associated with cholesterol deficiency during gestation: implications of Hedgehog signaling

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