The ceramide synthase 2b gene mediates genomic sensing and regulation of sphingosine Levels during zebrafish embryogenesis

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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 (sphk2^MZ) display early developmental phenotypes, including a delay in epiboly, depleted S1P levels, elevated levels of sphingosine, and resistance to sphingosine toxicity. The sphk2^MZ embryos also have strikingly increased levels of maternal transcripts encoding ceramide synthase 2b (Cers2b), and loss of Cers2b in sphk2^MZ embryos phenocopies sphingosine toxicity. An upstream region of the cers2b promoter supports enhanced expression of a reporter gene in sphk2^MZ 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 sphk2^MZ 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.

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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.
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.
Yu Hisano

Vascular Biology Program, Boston Children's Hospital, Boston, United States

Competing interests
The authors declare that no competing interests exist.
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.
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.
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.
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.

"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.

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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.