A mutation in zebrafish hmgcr1b reveals a role for isoprenoids in vertebrate heart-tube formation.
In vertebrates, the morphogenetic assembly of the primitive heart tube requires the medial migration and midline fusion of the bilateral myocardial epithelia. Several mutations that result in abnormal heart-tube formation have been studied; however, an understanding of the underlying molecular and cellular mechanisms of the migration and fusion of these epithelial sheets is far from complete. In a forward genetic screen to identify genes regulating early zebrafish heart development, we identified a mutation in the 3-hydroxy-3-methylglutaryl-Coenzyme A reductase 1b (hmgcr1b) gene that affects myocardial migration to the midline and subsequent heart-tube morphogenesis. The mutant phenotype can be rescued with injections of mevalonate, the direct product of HMGCR activity. Furthermore, treatment of embryos with pharmacological inhibitors of isoprenoid synthesis, which occurs downstream of mevalonate production, resulted in defective heart-tube formation. Interestingly, in hmgcr1b mutant embryos and embryos treated with HMGCR inhibitors, both RasCT20-eGFP and RhoaCT32-eGFP fusion proteins were mislocalized away from the plasma membrane in embryonic myocardial cells. We conclude that protein prenylation, acting downstream of Hmgcr1b and possibly through Ras and, or, Rho signaling, is required for the morphogenesis of the myocardial sheets for formation of the primitive heart tube.
D'Amico
Leonard
L
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, 1550 Fourth Street, San Francisco, California 94158, USA.
Scott
Ian C
IC
Jungblut
Benno
B
Stainier
Didier Y R
DY
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D002465:Cell Movement; D004625:Embryo, Nonmammalian / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008798:Mevalonic Acid; D008969:Molecular Sequence Data; D009024:Morphogenesis; D009206:Myocardium / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology; D010641:Phenotype; D017354:Point Mutation; D017368:Protein Prenylation; D016415:Sequence Alignment; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000378:metabolism*
D029961:Zebrafish Proteins; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid