Functional analysis of the zebrafish ortholog of HMGCS1 reveals independent functions for cholesterol and isoprenoids in craniofacial development

Quintana, A.M., Hernandez, J.A., Gonzalez, C.G.
PLoS One   12: e0180856 (Journal)
Registered Authors
Quintana, Anita
Cholesterol, Embryos, Isoprenoids, Cartilage, Face, Zebrafish, Fertilization, Larvae
MeSH Terms
  • Animals
  • Anticholesteremic Agents/pharmacology
  • Atorvastatin/pharmacology
  • Benzophenones/pharmacology
  • Body Patterning/drug effects
  • Body Patterning/genetics
  • Cell Differentiation/drug effects
  • Cholesterol/biosynthesis*
  • Chondrocytes/drug effects
  • Chondrocytes/metabolism
  • Chondrocytes/pathology
  • Craniofacial Abnormalities/genetics*
  • Craniofacial Abnormalities/metabolism
  • Craniofacial Abnormalities/pathology
  • Embryo, Nonmammalian
  • Enzyme Inhibitors/pharmacology
  • Gene Expression Regulation, Developmental
  • Hedgehog Proteins/genetics*
  • Hedgehog Proteins/metabolism
  • Humans
  • Hydroxymethylglutaryl CoA Reductases/genetics*
  • Hydroxymethylglutaryl CoA Reductases/metabolism
  • Hydroxymethylglutaryl-CoA Synthase/genetics*
  • Hydroxymethylglutaryl-CoA Synthase/metabolism
  • Neural Crest/drug effects
  • Neural Crest/metabolism
  • Neural Crest/pathology
  • Piperidines/pharmacology
  • Pyridines/pharmacology
  • Signal Transduction
  • Terpenes/antagonists & inhibitors
  • Terpenes/metabolism*
  • Zebrafish
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • Zinc Finger Protein GLI1/genetics*
  • Zinc Finger Protein GLI1/metabolism
28686747 Full text @ PLoS One
There are 8 different human syndromes caused by mutations in the cholesterol synthesis pathway. A subset of these disorders such as Smith-Lemli-Opitz disorder, are associated with facial dysmorphia. However, the molecular and cellular mechanisms underlying such facial deficits are not fully understood, primarily because of the diverse functions associated with the cholesterol synthesis pathway. Recent evidence has demonstrated that mutation of the zebrafish ortholog of HMGCR results in orofacial clefts. Here we sought to expand upon these data, by deciphering the cholesterol dependent functions of the cholesterol synthesis pathway from the cholesterol independent functions. Moreover, we utilized loss of function analysis and pharmacological inhibition to determine the extent of sonic hedgehog (Shh) signaling in animals with aberrant cholesterol and/or isoprenoid synthesis. Our analysis confirmed that mutation of hmgcs1, which encodes the first enzyme in the cholesterol synthesis pathway, results in craniofacial abnormalities via defects in cranial neural crest cell differentiation. Furthermore targeted pharmacological inhibition of the cholesterol synthesis pathway revealed a novel function for isoprenoid synthesis during vertebrate craniofacial development. Mutation of hmgcs1 had no effect on Shh signaling at 2 and 3 days post fertilization (dpf), but did result in a decrease in the expression of gli1, a known Shh target gene, at 4 dpf, after morphological deficits in craniofacial development and chondrocyte differentiation were observed in hmgcs1 mutants. These data raise the possibility that deficiencies in cholesterol modulate chondrocyte differentiation by a combination of Shh independent and Shh dependent mechanisms. Moreover, our results describe a novel function for isoprenoids in facial development and collectively suggest that cholesterol regulates craniofacial development through versatile mechanisms.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes