Germ cell migration in zebrafish is dependent on HMGCoA reductase activity and prenylation

Juanita L Thorpe, Maria Doitsidou, Shiu-Ying Ho, Eraz Raz, Steven A Farber

Research output: Contribution to journalArticlepeer-review

Abstract

Hydroxymethylglutaryl coenzyme A reductase (HMGCoAR) is required for isoprenoid and cholesterol biosynthesis. In Drosophila, reduced HMGCoAR activity results in germ cell migration defects. We show that pharmacological HMGCoAR inhibition alters zebrafish development and germ cell migration. Embryos treated with atorvastatin (Lipitor) exhibited germ cell migration defects and mild morphologic abnormalities. The effects induced by atorvastatin were completely rescued by prior injection of mevalonate, the product of HMGCoAR activity, or the prenylation precursors farnesol and geranylgeraniol. In contrast, squalene, a cholesterol intermediate further down the pathway, failed to rescue statin-induced defects. Moreover, pharmacologic inhibition of geranylgeranyl transferase 1 (GGT1) protein prenylation activity also resulted in abnormal germ cell migration. Thus, our pharmacological inhibition-and-rescue approach provided detailed information about the elements of isoprenoid biosynthesis that contribute to germ cell migration. Together with data from Drosophila (Santos and Lehmann, this issue), our results highlight a conserved role for protein geranylgeranylation in this context.

Original languageEnglish
Pages (from-to)295-302
Number of pages8
JournalDevelopmental Cell
Volume6
Issue number2
Publication statusPublished - Feb 2004

Keywords

  • Animals
  • Anticholesteremic Agents
  • Atorvastatin Calcium
  • Cell Movement
  • Chemokine CXCL12
  • Chemokines, CXC
  • Diterpenes
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Embryo, Nonmammalian
  • Enzyme Inhibitors
  • Farnesol
  • Germ Cells
  • Heptanoic Acids
  • Hydroxymethylglutaryl CoA Reductases
  • Mevalonic Acid
  • Microinjections
  • Morpholines
  • Protein Prenylation
  • Pyrroles
  • RNA, Messenger
  • RNA-Binding Proteins
  • Somites
  • Time Factors
  • Zebrafish
  • Zebrafish Proteins
  • gamma-Glutamyltransferase

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