PUBLICATION
Inhibition of the 3-hydroxy-3-methyl-glutaryl-CoA reductase induces orofacial defects in zebrafish
- Authors
- Signore, I.A., Jerez, C., Figueroa, D., Suazo, J., Marcelain, K., Cerda, O., Flores, A.C.
- ID
- ZDB-PUB-160805-4
- Date
- 2016
- Source
- Birth defects research. Part A, Clinical and molecular teratology 106(10): 814-830 (Journal)
- Registered Authors
- Keywords
- HMGCR, SHh-signaling, cholesterol pathway, orofacial cleft, orofacial malformation, statins, zebrafish
- MeSH Terms
-
- Abnormalities, Drug-Induced*/enzymology
- Abnormalities, Drug-Induced*/genetics
- Animals
- Atorvastatin/adverse effects*
- Atorvastatin/pharmacology
- Cleft Lip*/chemically induced
- Cleft Lip*/enzymology
- Cleft Lip*/genetics
- Cleft Lip*/pathology
- Cleft Palate*/chemically induced
- Cleft Palate*/enzymology
- Cleft Palate*/genetics
- Cleft Palate*/pathology
- Hydroxymethylglutaryl CoA Reductases*/genetics
- Hydroxymethylglutaryl CoA Reductases*/metabolism
- Mutation*
- Zebrafish*/genetics
- Zebrafish*/metabolism
- Zebrafish Proteins*/antagonists & inhibitors
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 27488927 Full text @ Birth Defects Res. Part A Clin. Mol. Teratol.
Citation
Signore, I.A., Jerez, C., Figueroa, D., Suazo, J., Marcelain, K., Cerda, O., Flores, A.C. (2016) Inhibition of the 3-hydroxy-3-methyl-glutaryl-CoA reductase induces orofacial defects in zebrafish. Birth defects research. Part A, Clinical and molecular teratology. 106(10):814-830.
Abstract
Background Orofacial clefts (OFCs) are common birth defects, which include a range of disorders with a complex etiology affecting formation of craniofacial structures. Some forms of syndromic OFCs are produced by defects in the cholesterol pathway. The principal enzyme of the cholesterol pathway is the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). Our aim is to study whether defects of HMGCR function would produce orofacial malformation similar to those found in disorders of cholesterol synthesis.
Methods We used zebrafish hmgcrb mutants and HMGCR inhibition assay using atorvastatin during early and late stages of orofacial morphogenesis in zebrafish. To describe craniofacial phenotypes, we stained cartilage and bone and performed in situ hybridization using known craniofacial markers. Also, we visualized neural crest cell migration in a transgenic fish.
Results Our results showed that mutants displayed loss of cartilage and diminished orofacial outgrowth, and in some cases palatal cleft. Late treatments with statin show a similar phenotype. Affected-siblings displayed a moderate phenotype, whereas early-treated embryos had a minor cleft. We found reduced expression of the downstream component of Sonic Hedgehog-signaling gli1 in ventral brain, oral ectoderm, and pharyngeal endoderm in mutants and in late atorvastatin-treated embryos.
Conclusion Our results suggest that HMGCR loss-of-function primarily affects postmigratory cranial neural crest cells through abnormal Sonic Hedgehog signaling, probably induced by reduction in metabolites of the cholesterol pathway. Malformation severity correlates with the grade of HMGCR inhibition, developmental stage of its disruption, and probably with availability of maternal lipids. Together, our results might help to understand the spectrum of orofacial phenotypes found in cholesterol synthesis disorders.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping