title: Long-chain Acyl-CoA synthetase 4A regulates Smad activity and dorsoventral patterning in the zebrafish embryo.
abstract: Long-chain polyunsaturated fatty acids (LC-PUFA) and their metabolites are critical players in cell biology and embryonic development. Here we show that long-chain acyl-CoA synthetase 4a (Acsl4a), an LC-PUFA activating enzyme, is essential for proper patterning of the zebrafish dorsoventral axis. Loss of Acsl4a results in dorsalized embryos due to attenuated bone morphogenetic protein (Bmp) signaling. We demonstrate that Acsl4a modulates the activity of Smad transcription factors, the downstream mediators of Bmp signaling. Acsl4a promotes the inhibition of p38 mitogen-activated protein kinase and the Akt-mediated inhibition of glycogen synthase kinase 3, critical inhibitors of Smad activity. Consequently, introduction of a constitutively active Akt can rescue the dorsalized phenotype of Acsl4a-deficient embryos. Our results reveal a critical role for Acsl4a in modulating Bmp-Smad activity and provide a potential avenue for LC-PUFAs to influence a variety of developmental processes.
authors: Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Embryology, Carnegie Institution for Science, Baltimore, MD 21218, USA.
authors: Rosa Linda
authors: RL
authors: Miyares
authors: Institute of Developmental Biology, University of Cologne, D-50674 Cologne, Germany.
authors: Cornelia
authors: C
authors: Stein
authors: Institute of Developmental Biology, University of Cologne, D-50674 Cologne, Germany.
authors: Björn
authors: B
authors: Renisch
authors: Department of Embryology, Carnegie Institution for Science, Baltimore, MD 21218, USA.
authors: Jennifer Lynn
authors: JL
authors: Anderson
authors: Institute of Developmental Biology, University of Cologne, D-50674 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, D-50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, D-50674 Cologne, Germany. Electronic address: matthias.hammerschmidt@uni-koeln.de.
authors: Matthias
authors: M
authors: Hammerschmidt
authors: Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Embryology, Carnegie Institution for Science, Baltimore, MD 21218, USA. Electronic address: farber@ciwemb.edu.
authors: Steven Arthur
authors: SA
authors: Farber
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019521:Body Patterning / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D008969:Molecular Sequence Data; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D000214:Acyl Coenzyme A; D019485:Bone Morphogenetic Proteins; D005231:Fatty Acids, Unsaturated; D051896:Smad Proteins, Receptor-Regulated; D016212:Transforming Growth Factor beta; D029961:Zebrafish Proteins; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase