Expression of sonic hedgehog downstream genes is modified in rat embryos exposed in utero to a distal inhibitor of cholesterol biosynthesis
| Autor: | Charles Roux, Françoise Gofflot, Wassila Gaoua, Jacques J. Picard, Loïc Bourguignon |
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| Rok vydání: | 2001 |
| Předmět: |
medicine.medical_specialty
animal structures Hindbrain Congenital Abnormalities trans-1 4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride Cholesterol Dietary Embryonic and Fetal Development Dehydrocholesterols Holoprosencephaly Pregnancy GLI1 Internal medicine medicine Animals Humans Hedgehog Proteins Sonic hedgehog In Situ Hybridization Embryonic Induction biology Anticholesteremic Agents Abnormalities Drug-Induced Gene Expression Regulation Developmental Proteins medicine.disease Phenotype Rats Cell biology Cholesterol Endocrinology Smith–Lemli–Opitz syndrome In utero embryonic structures Forebrain Trans-Activators biology.protein Female Developmental Biology |
| Zdroj: | Developmental Dynamics. 220:99-111 |
| ISSN: | 1097-0177 1058-8388 |
| DOI: | 10.1002/1097-0177(2000)9999:9999<::aid-dvdy1092>3.0.co;2-g |
| Popis: | Holoprosencephaly is a common developmental anomaly of the forebrain and midface, that has been associated with mutations in the Sonic Hedgehog gene, and with perturbations of cholesterol synthesis and metabolism in mammalian embryos. The study presented here was aimed to evaluate the functional relationship between these two causal agents in the genesis of the phenotype. Therefore, we used rat embryos exposed in utero to a distal inhibitor of cholesterol biosynthesis (AY9944) in which we analyzed different Shh-dependent processes, as evaluated by the expression of eight target genes. In addition, to delineate between the impact of cholesterol shortage and/or sterol precursors accumulation on the Shh signaling cascade we exposed rat embryos to AY9944 and we provided complementary diets rich in cholesterol and 7-DHC. At the early-somite stage we observed a reduction of Shh signaling in AY9944 treated embryos, resulting in the definition of a narrower ventral domain. Later in development this reduction of Shh signaling led to a complete interruption of the pathway in the rostral hindbrain and caudal midbrain. Other regions such as the forebrain and the spinal cord appeared less sensitive to the reduction of Shh signaling and interruption of the pathway was only observed in a subset of embryos. Finally, we did provide evidence that 7-DHC accumulation is compatible with normal activity of Shh, as long as cholesterol levels in embryonic tissue is sufficient. |
| Databáze: | OpenAIRE |
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