1. Biochemistry and Chemical Biology
  2. Developmental Biology
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The ceramide synthase 2b gene mediates genomic sensing and regulation of sphingosine Levels during zebrafish embryogenesis

  1. Karen Mendelson
  2. Suveg Pandey
  3. Yu Hisano
  4. Frank Carellini
  5. Bhaskar Das
  6. Timothy Hla  Is a corresponding author
  7. Todd Evans  Is a corresponding author
  1. Cornell University, United States
  2. Boston Children's Hospital, United States
  3. Icahn School of Medicine at Mount Sinai, United States
Research Article
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Cite this article as: eLife 2017;6:e21992 doi: 10.7554/eLife.21992

Abstract

Sphingosine-1-phosphate (S1P) is generated through phosphorylation of sphingosine by sphingosine kinases (Sphk1 and Sphk2). We show that sphk2 maternal-zygotic mutant zebrafish embryos (sphk2MZ) display early developmental phenotypes, including a delay in epiboly, depleted S1P levels, elevated levels of sphingosine, and resistance to sphingosine toxicity. The sphk2MZ embryos also have strikingly increased levels of maternal transcripts encoding ceramide synthase 2b (Cers2b), and loss of Cers2b in sphk2MZ embryos phenocopies sphingosine toxicity. An upstream region of the cers2b promoter supports enhanced expression of a reporter gene in sphk2MZ embryos compared to wildtype embryos. Furthermore, ectopic expression of Cers2b protein itself reduces activity of the promoter, and this repression is relieved by exogenous sphingosine. Therefore, the sphk2MZ genome recognizes the lack of sphingosine kinase activity and up-regulates cers2b as a salvage pathway for sphingosine turnover. Cers2b can also function as a sphingolipid-responsive factor to mediate at least part of a feedback regulatory mechanism.

Article and author information

Author details

  1. Karen Mendelson

    Department of Surgery, Weill Cornell Medical College, Cornell University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Suveg Pandey

    Department of Surgery, Weill Cornell Medical College, Cornell University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yu Hisano

    Vascular Biology Program, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Frank Carellini

    Department of Surgery, Weill Cornell Medical College, Cornell University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Bhaskar Das

    Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Timothy Hla

    Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, United States
    For correspondence
    timothy.hla@childrens.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
  7. Todd Evans

    Department of Surgery, Weill Cornell Medical College, Cornell University, New York, United States
    For correspondence
    tre2003@med.cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7148-9849

Funding

National Institutes of Health (HL089934)

  • Timothy Hla

National Institutes of Health (CA077839)

  • Timothy Hla

National Institutes of Health (HL111400)

  • Todd Evans

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (2011-100) of the Weill Cornell Medical College.

Reviewing Editor

  1. Didier YR Stainier, Max Planck Institute for Heart and Lung Research, Germany

Publication history

  1. Received: September 30, 2016
  2. Accepted: September 25, 2017
  3. Accepted Manuscript published: September 28, 2017 (version 1)
  4. Accepted Manuscript updated: October 3, 2017 (version 2)
  5. Version of Record published: October 20, 2017 (version 3)

Copyright

© 2017, Mendelson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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