Molecular mechanisms underlying limb anomalies associated with cholesterol deficiency during gestation: implications of Hedgehog signaling.
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.
Unit of Developmental Genetics, Université Catholique de Louvain, 73 Avenue Mounier, UCL-7383, 1200 Brussels, Belgium. francoise.gofflot@gede.ucl.ac.be
Françoise
F
Gofflot
Carine
C
Hars
Françoise
F
Illien
Françoise
F
Chevy
Claude
C
Wolf
Jacques J
JJ
Picard
Charles
C
Roux
D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities; D002784:Cholesterol / Q000172:deficiency*; D004305:Dose-Response Relationship, Drug; D053823:Hedgehog Proteins; D000960:Hypolipidemic Agents / Q000494:pharmacology; D018878:Limb Buds; D017880:Limb Deformities, Congenital / Q000209:etiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D013723:Teratogens / Q000494:pharmacology; D015534:Trans-Activators / Q000502:physiology*; D014308:Triparanol / Q000494:pharmacology
D053823:Hedgehog Proteins; D000960:Hypolipidemic Agents; C509239:SHH protein, human; D013723:Teratogens; D015534:Trans-Activators; D014308:Triparanol; D002784:Cholesterol